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EP2795332A2 - Marker sequences for breast cancer and the use thereof - Google Patents

Marker sequences for breast cancer and the use thereof

Info

Publication number
EP2795332A2
EP2795332A2 EP12818894.3A EP12818894A EP2795332A2 EP 2795332 A2 EP2795332 A2 EP 2795332A2 EP 12818894 A EP12818894 A EP 12818894A EP 2795332 A2 EP2795332 A2 EP 2795332A2
Authority
EP
European Patent Office
Prior art keywords
homo sapiens
breast cancer
protein
sequences
isoform
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12818894.3A
Other languages
German (de)
French (fr)
Inventor
Angelika LÜKING
Axel Kowald
Annabel HÖPNER
Christian Scheer
Heidelinde Fiegl
Günter Daxenbichler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Protagen GmbH
Original Assignee
Protagen GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Protagen GmbH filed Critical Protagen GmbH
Priority to EP12818894.3A priority Critical patent/EP2795332A2/en
Publication of EP2795332A2 publication Critical patent/EP2795332A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the present invention relates to a method for
  • marker sequences for breast cancer Identification of marker sequences for breast cancer, the marker sequences identified by this method and their diagnostic use, diagnostic devices containing marker sequences for breast cancer, in particular an assembly and a protein array and their use.
  • the invention relates to methods for screening potential drugs for the treatment and prevention of breast cancer by means of these marker sequences.
  • Protein arrays are gaining increasing industrial importance in analytics and diagnostics as well as in pharmaceutical development. Protein arrays have become established as screening tools.
  • Protein arrays make it necessary to have the required proteins available.
  • protein expression libraries have been established for this purpose. High throughput z cloning of defined open reading frames is one
  • GATEWAY recombinational cloning application to the cloning of large numbers of open reading frames or ORFeems. Methods Enzymol, 328, 575-592).
  • ORFeems open reading frames
  • Methods Enzymol, 328, 575-592 are strongly related to the progress of the genome sequencing proce- dures and the annotation of these gene sequences.
  • determination of the expressed sequence is due
  • the cDNA of a particular tissue in a bacterial or a eukaryotic expression vector, such as yeast, is cloned.
  • the vectors used for the expression are generally characterized by the fact that they carry inducible promoters, with which the timing of protein expression can be controlled.
  • expression vectors have sequences for so-called
  • Affinity epitopes or proteins on the one hand for the specific detection of the recombinant fusion proteins by means of a directed against the affinity epitope
  • Antibody on the other hand becomes the specific one
  • antibody-presenting arrays are also described (Lal et al (2002) Antibody arrays: An embryonic but growing technology, DDT, 7, 143-149, Kusnezow et al., (2003) Antibody microarrays: An evaluation of production parameters, Proteomics, 3, 254-264).
  • Breast cancer is the most common malignant tumor of the human mammary gland. He occurs mainly in women; Only about one hundred of these cancers occur in men. Breast cancer is the most common cancer in women in the Western world and more women die from breast cancer than from another cancer. Most diseases occur sporadically (by chance), but there are both inherited and acquired risk factors. Numerous national and international programs for early detection and structured treatment aim to reduce mortality.
  • breast cancer early diagnosis is crucial for the further course of disease and prognosis. Although many tumor markers are associated with breast cancer, they are not suitable for early diagnosis because of their low specificity. They are mainly used to monitor disease progression or response to therapy.
  • US 2003/198972 Al discloses the identification and use of gene expression patterns associated with various stages of breast cancer.
  • the expression patterns are analyzed by comparative analysis of gene expression in healthy individuals or patients with benign changes and breast cancer
  • Microarrays which are equipped with polynucleotides, brought into contact. The intensity pattern is analyzed and allows assignment to different stages of breast cancer.
  • US 2012/021887 discloses the use of arrays and protein microarrays with marker sequences for breast cancer for the detection of breast cancer-specific autoantibodies. But there is still a need for
  • the invention relates to a method for identifying marker sequences for breast cancer, characterized in that a. Marker sequence candidates for breast cancer by
  • identifying a carrier on which at least 1,000 different proteins are immobilized being contacted with a serum sample from a breast cancer patient and identifying proteins that interact with the serum (marker sequence candidates), and b. the interaction of one or more marker sequence candidates from a. with the serum of patients with
  • Breast cancer is determined as compared to the interaction of the marker sequence candidate from a. with the serum of patients with benign alterations and the interaction of the marker sequence candidate from a. with serum from healthy controls, and c. Marker sequences are identified by being different with the serum from breast cancer patients
  • Control persons on the support according to a. simultaneously at least 5,000, preferably at least 10,000 different proteins immobilized simultaneously.
  • marker sequences for breast cancer are identified which are specific for breast cancer with a high risk of metastasis.
  • Marker sequences are identified for breast cancer that are highly specific. Marker sequences that are found with this method, on the one hand enable the early
  • breast cancer e.g. of its precursors and on the other hand, the distinction of breast cancer or its
  • marker sequences for breast cancer can be identified with the method according to the invention, which already at an early stage make it possible to predict the course and / or the risk of metastasis formation. Predicting the risk of metastasis also allows for improved therapy and targeted patient monitoring
  • the marker sequences of the invention are useful for the analysis of body fluids, e.g. Serum particularly suitable. This is a fast and easy way
  • the invention also relates to the
  • the invention provides marker sequences for breast cancer obtainable by an inventive
  • the invention also provides an arrangement comprising one or more marker sequences according to the invention.
  • the invention also provides a protein array comprising one or more marker sequences according to the invention.
  • the invention also provides a diagnostic agent comprising one or more marker sequences according to the invention and optionally further additives and / or auxiliaries.
  • the invention also provides a test kit comprising one or more marker sequences according to the invention and
  • the invention is also an inventive
  • the invention also provides an inventive
  • the subject of the invention is also a diagnostic agent according to the invention, characterized in that 2 or 3,
  • the invention also provides a test kit according to the invention characterized in that 2 or 3, preferably 4 or 5, more preferably 7 or 8 or more different
  • the invention also provides the use of one or more marker sequences according to the invention, one
  • Protein arrays a diagnostic agent according to the invention or a test kit according to the invention for early detection, diagnosis, prognosis, therapy control and / or aftercare in breast cancer.
  • the invention also provides the use of one or more marker sequences according to the invention, one
  • Protein arrays Protein arrays, a diagnostic agent according to the invention or a test kit according to the invention for distinguishing
  • the invention also provides the use of one or more marker sequences according to the invention, one
  • Protein arrays Protein arrays, a diagnostic agent of the invention or a test kit according to the invention for individualized
  • Patient groups cohorts, populations, breast cancer variants, stages of breast cancer.
  • the invention also provides the use of one or more marker sequences according to the invention, one A device according to the invention, a protein array according to the invention, a diagnostic agent of the invention or a test kit according to the invention for detecting and / or determining the amount of one or more autoantibodies associated with breast cancer, for example in
  • Body fluids such as serum, tissue or tissue extracts of the patient.
  • the invention also provides the use of one or more marker sequences according to the invention, one
  • Protein arrays Protein arrays, a diagnostic agent of the invention or a test kit according to the invention for the analysis of
  • Autoantibodies and / or for monitoring changes in autoantibody profiles for example in body fluids such as serum, tissue or tissue extracts of the patient.
  • the invention also provides the use of one or more marker sequences according to the invention, one
  • Protein arrays a diagnostic agent of the invention or a test kit according to the invention for the screening of substances (drugs) for breast cancer.
  • the invention also provides a target for the treatment and / or therapy of breast cancer, wherein the target of the marker sequences of the invention SEQ ID No. 1-1473 and
  • Protein sequences and sequences encoded by SEQ ID no. 1 - 491, partial sequences thereof and their homologues are selected.
  • the invention also provides a method for
  • one or more marker sequence (s) selected from the group comprising the sequences SEQ ID NO. 1 - 1473 and
  • Protein sequences and sequences encoded by SEQ ID no. 1 - 491, partial sequences thereof and their homologues are applied to a carrier,
  • the breast cancer-specific marker sequences SEQ ID No. 1 - 491 has been described here for the first time. All of these sequences have in common that they have been identified by means of a protein array and the method described in the examples. The invention therefore relates in particular breast cancer-specific markers ⁇ sequence selected from the sequences
  • SEQ ID no. 1-491 comprising SEQ ID no. 1-491 and partial sequences of SEQ ID No. 1-491 with at least 90%, preferably 95% of the length of the sequences SEQ ID NO. 1-491 and homologs of SEQ ID No. 1-
  • the invention thus provides marker sequences and arrangements of marker sequences for breast cancer which can be used as part of individualized diagnostics and therapy, for example in the case of different patients, patient groups, cohorts, population groups,
  • breast cancer variants targeted and customized to diagnose breast cancer and to monitor the therapy.
  • Marker sequence (s) is / are selected from the sequences SEQ ID NO. 1 - 1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID NO. 1 - 1473 and homologs of SEQ ID No. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more, to the corresponding ones Sequences and proteins / peptides encoded by the sequences SEQ ID no. 1 - 491, encoded by their partial sequences and homologues for breast cancer diagnosis and therapy, in particular for the early detection of breast cancer, for the diagnosis of breast cancer, for the prognosis, for example of the risk of
  • the invention also relates to the detection and determination of the amount of at least two different autoantibodies in a patient, correspondingly at least two
  • the invention is also an inventive
  • SEQ ID no. 1 to 1473 is / are selected from group SEQ ID no. 1 to 1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID NO. 1 - 1473 and
  • the invention is also an inventive
  • breast cancer-specific marker sequence wherein at least 2, for example 3 to 5 or 10, preferably 30 to 50 or 50 to 100 or more breast cancer-specific
  • Marker sequences are determined on or to a patient to be examined.
  • the invention is also an inventive
  • breast cancer specific marker sequence (s) are / are applied to a solid support, in particular a filter, membrane, bead or small platelet or bead, for example a magnetic or
  • Fluorophore-labeled beads a silicon wafer, glass, metal, plastic, a chip, a mass spectrometric target or a matrix.
  • a particular embodiment relates to the use of a filter as a solid support.
  • a filter As a filter, PVDF, nitrocellulose or nylon is further preferred (e.g., Immobilon P
  • Breast cancer specific marker sequence present as clone (s). Therefore, the invention relates to the use of breast cancer-specific marker sequences for the diagnosis of
  • Breast cancer being at least one breast cancer-specific
  • Marker sequence of a DNA, in particular cDNA selected from the group SEQ ID No. 1-491 or RNA selected from the group 492-982 or a partial sequence or a fragment or a homologous sequence thereof is determined on or to a patient to be examined.
  • breast cancer-specific marker sequences also called marker sequences according to the invention
  • the breast cancer-specific marker sequences according to the invention were able to be detected by differential screening of samples, namely healthy subjects, with patient samples containing breast cancer
  • these marker sequences according to the invention could be detected for the first time by means of protein arrays (see
  • the invention also provides a method for
  • Identification of marker sequences for breast cancer comprising the steps of a) providing sequences on an array, b) identifying marker sequence candidates for
  • breast cancer-specific marker sequences include a group of diseases that may be precursors to breast cancer and their establishment as breast cancer, breast cancer (as defined, for example, in US Pat
  • the marker sequences according to the invention can also be combined, supplemented or extended with known biomarkers for this indication. However, at least 50%,
  • Protein array the diagnostic agent according to the invention or the test kit according to the invention.
  • test kit the test kit according to the invention.
  • the arrangement according to the invention, the assay and protein array according to the invention and the use according to the invention represent at least 75%, preferably 80% or 85%, particularly preferably 90% or 95% of marker sequences according to the invention.
  • the determination of the breast cancer-specific marker sequences takes place outside the human body and the determination takes place in an ex vivo / in vitro diagnosis.
  • the invention also relates to an assay or protein array comprising an arrangement / use according to the invention.
  • the invention relates to a diagnostic device and / or an assay, in particular a protein array for
  • the invention also relates to the use of a
  • inventive arrangement or an assay or protein array according to the invention for the analysis of Autoantibody profiles of patients, in particular for
  • the invention also provides a diagnostic (test kit) for the early detection and / or diagnosis of breast cancer and / or
  • Prognosis and / or prediction of the risk of metastasis formation in breast cancer comprising an arrangement according to the invention, preferably on a carrier or an assay or protein array according to the invention and, if appropriate, further additives and auxiliaries.
  • the invention also provides a diagnostic (test kit) for monitoring therapy and / or aftercare in breast cancer comprising an arrangement according to the invention or a
  • inventive assay or protein array and optionally other additives and excipients.
  • the invention relates to the use of breast cancer-specific
  • Marker sequence of a cDNA selected from the group SEQ ID No. 1-491 (clone sequences) or SEQ ID No. 492-982 (RNA) or one each by SEQ ID No. 1-982 is a coded protein or each a partial sequence or fragment thereof.
  • the invention also provides a method for
  • one or more breast cancer-specific marker sequences selected from the group of the sequences SEQ ID NO. 1 - 1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID NO. 1 - 1473 and homologues of SEQ ID no. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more of the corresponding sequences and proteins / peptides encoded by the sequences SEQ ID NO. 1-491, encoded by their partial sequences and homologues are applied to a support and
  • One or more breast cancer specific marker sequences are used in a method of diagnosis and / or in a diagnostic and / or a test kit.
  • Marker sequences used together or in combination, for example, directly in series or in parallel.
  • a particular embodiment of the invention relates to the method, wherein stratification or therapy control Decisions for treatment and therapy of the patient, in particular hospitalization of the patient, use, effect and / or dosage of one or more drugs, a therapeutic measure or the monitoring of a patient
  • Classification of a disease including prognosis includes. Furthermore, the invention relates to a method for stratifying, in particular for risk stratification and / or
  • therapy control also includes the classification of patients into responders and non-responders with regard to a therapy or its course of therapy.
  • Diagnosis in the sense of this invention means the positive detection of breast cancer by means of the breast cancer-specific marker sequences according to the invention and the assignment of the patients to breast cancer.
  • diagnosis includes medical diagnosis and investigations in this regard, in particular in vitro diagnostics and laboratory diagnostics Proteomics and nucleic acid blots
  • diagnosis also includes the differential diagnosis of breast cancer by means of the breast cancer-specific invention
  • Stratification also: stratification or therapy control
  • stratification means that, for example, the methods according to the invention allow decisions for the treatment and therapy of the patient, be it hospitalization of the patient, use, effect and / or dosage of one or more drugs, a therapeutic one Measure or the monitoring of a course of disease as well as course of therapy or etiology or classification of a disease, eg in a new or existing subtype or the differentiation of diseases and their patients.
  • the term "stratification" includes in particular the
  • Prognosis means the prediction of disease progression, for example the prediction of recurrence-free survival, overall survival, the risk of metastasis formation.
  • patient is understood to mean any test person - human or mammal - with the proviso that the subject is examined for breast cancer.
  • breast cancer-specific marker sequence in the sense of this invention means that the nucleic acid, for example DNA, in particular cDNA or RNA or the encoded amino acid sequence or the respective polypeptide or protein obtainable therefrom is significantly (specifically) for
  • Breast cancer-specific marker sequences may be nucleic acid sequences and amino acid sequences, including modifications.
  • Breast cancer-specific and “for breast cancer” means that, for example, the cDNA or the respectively obtainable polypeptide or protein interact with substances from the body fluid or tissue extract of a patient with breast cancer (eg antigen (epitope) / antibody
  • Body fluid or tissue excision occur either only or at least increased in breast cancer or are expressed, whereas these substances are not present in patients without breast cancer, or at least to a lesser extent (smaller amount, lower concentration).
  • ⁇ breast cancer-specific marker sequences may also be characterized on the other hand that they interact with
  • Breast cancer-specific marker sequences may also be present in healthy volunteers, but their amount (concentration) changes, for example, in the development, establishment and therapy of breast cancer.
  • the breast cancer-specific marker sequences are therefore biomarkers for breast cancer.
  • the breast cancer ⁇ specific marker sequences can in this way a profile of substances from body fluid and tissue extract
  • Autoantibody profile includes the amount of one or more
  • Breast cancer-associated autoantibody profiles thus include on the one hand the composition (one or more
  • the breast cancer-specific marker sequence is an antigen or a part of an antigen or encodes an antigen or a part of an antigen.
  • the breast cancer-specific marker sequence recognizes / binds to autoantibodies present (enhanced), or to a lesser extent (or no longer), in the course of genesis, establishment and therapy of breast cancer (hereinafter "breast cancer-associated autoantibodies Autoantibodies are formed by the body against the body's own antigens, which are produced, for example, in breast cancer.Autoantibodies are formed by the body against different substances and pathogens. [Vor Treatment Im] In the context of the present invention, in particular the breast cancer-associated autoantibodies which are detected on the occurrence and in the course of time the formation of breast cancer are formed
  • Breast cancer-associated autoantibodies can be detected using the methods of the invention and
  • Breast cancer-specific marker sequences are detected and thus serve as an indication for breast cancer.
  • the detection and monitoring of the amount of breast cancer-associated marker sequences are detected and thus serve as an indication for breast cancer.
  • Autoantibodies in the patient can be used for early detection, diagnosis and / or therapy monitoring / therapy control and for
  • breast cancer-associated autoantibody profile In other cases, two or more breast cancer-specific marker sequences will be necessary to map a breast cancer-associated autoantibody profile.
  • the breast cancer-associated autoantibodies can be detected with breast cancer specific marker sequences derived from another individual, for example, from a commercial cDNA library.
  • Embodiments of the invention relate to the breast cancer-associated marker sequences SEQ ID No. 1-491, SEQ ID. No. 492-982 and / or partial sequences of SEQ ID No. 1 - 982, and sequences coding for the proteins SEQ ID No. 983 to 1473 and / or partial sequences of these proteins.
  • the breast cancer-associated autoantibodies can be detected with breast cancer specific marker sequences derived from the same individual (autoantigen), for example, from a patient specific or a group of patients (e.g.
  • Autoantibodies can be formed by the patient many years before the onset of the first disease symptoms. This would be an early detection, diagnosis and also prognosis and
  • the invention Devices and means (array, array, protein array, diagnostic, test kit) and methods thus allow very early intervention compared to known methods, which significantly improves prognosis and survival rates.
  • the invention also makes it possible to detect and monitor breast cancer at any stage of its development and treatment, as well as under surveillance
  • the agents of the invention also allow for easy home handling by the patient and cost-effective routine screening for early detection.
  • Each patient may have one or more different autoantibodies associated with breast cancer in the course of breast cancer and the progression of breast cancer
  • composition and / or the amount of breast cancer-specific autoantibodies formed in the course of breast cancer development and progression of the disease change so that a quantitative evaluation is necessary.
  • Therapy / treatment of breast cancer leads to changes in the composition and / or amount of breast cancer-associated autoantibodies.
  • breast cancer-specific marker sequences according to the invention enable the individual compilation of breast cancer-specific marker sequences in an arrangement for individual patients, groups of patients, specific cohorts,
  • breast cancer-associated autoantibodies can be detected using the corresponding antigens / autoantigens in
  • Such an interaction is for example a bond, in particular a binding substance at least one breast cancer specific marker sequence or in case the breast cancer specific marker sequence has one
  • Nucleic acid for example a cDNA
  • a suitable substance under chosen conditions, in particular stringent conditions (for example as usual
  • Hybridization conditions is hybridization in 4 x SSC at 37 ° C followed by several washing steps in 1 x SSC
  • Tissue extraction of a patient and the breast cancer specific marker sequences is preferably a protein-protein
  • Such substances for example antigens, autoantigens, breast cancer-associated autoantibodies, are part of a body fluid, in particular blood, according to the invention.
  • Cerebrospinal fluid, synovial fluid or a tissue extract for example from tumor tissue of the patient.
  • the invention relates to the use of these body fluids and tissue extracts for early detection, diagnosis, prognosis, therapy control and aftercare.
  • the breast cancer-specific marker sequences or the substances recognized by these marker sequences for example breast cancer-associated autoantibodies, may be present at a significantly higher or lower expression rate or concentration, which indicates breast cancer.
  • proteomics or nucleic acid blots the relative
  • Marker sequences detected substances determined.
  • the protein is preferred for a protein
  • RNA breast cancer-specific marker sequences according to the invention are the subject of Table A (RNA) and can be clearly identified by the respectively cited database entry (also by means of the Internet: http://www.ncbi.nlm.nih.gov/) (by means of accession no.). , see also the corresponding
  • the invention also encompasses the full-length sequences of the breast cancer-specific marker sequences according to the invention, namely as defined by the known database entry according to Table A, SEQ ID NO. 1 - 1473 called. Furthermore, therefore, also include analog
  • SEQ 1 -1473 again represent partial sequences, at least with high homology.
  • the breast cancer-specific marker sequences SEQ 1-1473 are preferred according to the invention.
  • the marker sequences also include such
  • nucleic acid sequence in particular cDNA sequence and the corresponding amino acid sequence, such as
  • the invention also relates to homologs of breast cancer-specific marker sequences and partial sequences, for example fragments of breast cancer-specific marker sequences.
  • Homologs are, for example, nucleic acid and / or nucleic acid
  • Protein sequences for example homologs of SEQ ID no. 1 - 1473, in particular homologs of SEQ ID No. 1-491 and SEQ ID No. 492-982 having an identity with the breast cancer ⁇ specific marker sequences of at least 70% or 80%, preferably 90% or 95%, more preferably 96% or 97% or more, for example 98% or 99%.
  • the homology in the event that the breast cancer-specific marker sequences are antigens the homology in the event that the breast cancer-specific marker sequences are antigens, the homology in the event that the breast cancer-specific marker sequences are antigens, the homology in the event that the breast cancer-specific marker sequences are antigens, the homology in the event that the breast cancer-specific marker sequences are antigens, the homology in
  • Sequence area in which the antigen-antibody or antigen-autoantibody interaction takes place at least 95%, preferably at least 97%, particularly preferably at least 99%.
  • Mutations such as base-exchange mutations, raster mutations, base insertion mutations, base-loss mutations,
  • the invention also subsequences of
  • fragments of the marker sequences according to the invention are those nucleic acids or proteins / peptides which are opposite to the complete nucleic acid or the
  • the deletion may be at or near the end and / or within the sequence.
  • partial sequences and / or fragments comprising 50 to 100 nucleotides, 70-120 nucleotides of a complete sequence, for example of SEQ ID 1473, are included. Homologs of partial sequences and fragments are also included according to the invention.
  • the breast cancer-specific marker sequences compared to the sequences 1-1473 are shortened so that they consist only of the / the binding sites for the relevant breast cancer associated autoantibodies.
  • Breast cancer-specific marker sequences which differ from the sequences SEQ ID no. 1 - 1473 in that they contain one or more insertions, the
  • Insertions for example, 1 to 100 or more
  • Nucleotides / amino acids preferably 5 to 50, more preferably 10 to 20 nucleotides / amino acids in length and the sequences otherwise identical or homologous to the
  • Sequences 1 - 1473 are. Particularly preferred
  • Partial sequences which are at least 90%, preferably at least 95%, particularly preferably at least 97% or 98%, of the length of the breast cancer-specific marker sequences according to the invention, SEQ ID no. 1 -491, SEQ ID. No. 492-982, SEQ ID No. 983 - 1473 exhibit. Also included according to the invention are homologs of the partial sequences.
  • Breast cancer-specific marker sequence may be represented in varying amounts in one or more regions in the array or on the carrier. This allows a variation of the sensitivity.
  • the regions may each comprise a total of breast cancer-specific marker sequences, i. a sufficient number of different breast cancer-specific marker sequences, in particular 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more different and optionally further
  • Nucleic acids and / or proteins in particular biomarkers.
  • Marker sequences and optionally further nucleic acids and / or proteins in particular biomarkers represented on the carrier. Also preferred are more than 2,500, more preferably 10,000 or more different or identical breast cancer-specific marker sequences and optionally further nucleic acids and / or proteins, in particular
  • Biomarker on the carrier represents.
  • the arrangement is such
  • breast cancer-specific marker sequences represented on the array in the form of a grid on present to a carrier are designed that the breast cancer-specific marker sequences represented on the array in the form of a grid on present to a carrier. Further, such arrangements
  • the breast cancer-specific marker sequences are spotted.
  • Such high density spotted assemblies are disclosed, for example, in WO 99/57311 and WO 99/57312, and may be advantageously used in a robotic automated high throughput method.
  • the term "assay" or diagnostic device also includes such
  • Embodiments of a device such as ELISA, bead-based assay, line assay, Western blot, immunochromatographic
  • Methods e.g., so-called lateral flow immunoassays or similar immunological single or multiplex detection methods.
  • a "protein array” in the sense of this invention is the
  • Solid support carrier sequences wherein the breast cancer specific marker sequences are proteins or peptides or portions thereof and wherein the carrier may be of any shape and / or size and wherein the carrier is preferably a solid carrier.
  • the breast cancer specific marker sequences of the assembly are fixed to a support, but preferably spotted or immobilized even printed, i. reproducible
  • One or more breast cancer-specific proliferative hormones are applied.
  • One or more breast cancer-specific proliferative hormones are applied.
  • One or more breast cancer-specific proliferative hormones are applied.
  • breast cancer-specific marker sequences be present and available in different amounts based on a spot. Furthermore, the breast cancer-specific marker sequences may be standardized on the carrier (eg by serial
  • a standard e.g., a gold standard
  • a standard may also be applied to the carrier.
  • the breast cancer specific marker sequences are present as clones.
  • Such clones can be obtained, for example, by means of a cDNA expression library according to the invention (Büssow et al., 1998
  • Expression vectors obtained from an expressing cDNA library consisting of the cDNA marker sequences.
  • Expression vectors preferably contain inducible
  • Promoters Induction of expression may be e.g. by means of an inductor, such as IPTG.
  • an inductor such as IPTG.
  • Expression vectors are described in Terpe et al. (Terpe T Appl Microbiol Biotechnol 2003 Jan; 60 (5): 523-33).
  • Expression libraries are known to the person skilled in the art, these can be prepared according to standard works, such as Sambrook et al., Molecular Cloning, Laboratory Laboratory, 2nd edition (1989), CSH press, Cold Spring Harbor, New York Further preferred are such expression libraries
  • tissue-specific eg human tissue, in particular human organs, for example from breast tissue or tissue from breast cancer
  • expression libraries are also included according to the invention, which can be obtained by exon trapping. Instead of expression library can be spoken synonymously from an expression bank.
  • protein arrays or corresponding expression libraries which have no redundancy (so-called: Uniclone® library) and can be prepared, for example, according to the teachings of WO 99/57311 and WO 99/57312. These preferred Uniclone libraries have a high content of non-defective, fully expressed proteins of a cDNA expression library.
  • the clones may not be such as transformed bacteria, recombinant phage or transformed cells of mammals, insects, fungi, yeasts or plants.
  • the clones are fixed on a solid support, spotted or immobilized. Therefore, the invention relates to a
  • Marker sequences are present as clones.
  • breast cancer-specific marker sequences may be in the form of a fusion protein
  • the day can be one such as c-myc, His-tag, Arg-tag, FLAG, alkaline
  • Phosphatase V5 tag, T7 tag or strep tag, HAT tag, NusA, S tag, SBP tag, thioredoxin, DsbA, a fusion protein,
  • this invention corresponds to a grid that the order of a microtiter plate (8-12 wells strips, 96 wells, 384 wells or more), one Has silicon wafers, a chip, a mass spectrometric target or a matrix.
  • the invention relates to an assay or protein array for identification and
  • Characterizing a substance for example, hit, conductive substance, candidate, active ingredient for breast cancer, characterized in that an arrangement or assay according to the invention with a. ) is brought into contact with at least one substance to be examined and b. ) a binding success is detected.
  • a substance for example, hit, conductive substance, candidate, active ingredient
  • the substance to be investigated may be any native or non-native biomolecule, a (synthetic) chemical molecule, a natural product, a mixture or a
  • Binding results interactions such as protein-protein interactions (e.g., breast cancer specific protein
  • Marker sequence such as antigen / antibody
  • reporter enzymes such as alkaline phosphatase
  • a readout is e.g. by means of a
  • Microarray laser scanner a CCD camera or visually.
  • the invention relates to a drug / prodrug or prodrug for breast cancer
  • the invention is also the use of a
  • Breast cancer-specific marker sequence selected from sequences SEQ ID No. 1 - 1473 and partial sequences from SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID No. 1 - 1473 and homologs of SEQ ID No. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more to the
  • the invention thus relates to the use of the marker sequences according to the invention, preferably in the form of an arrangement, as an affinity material for carrying out a
  • Body fluids of a patient with breast cancer such as blood or plasma, bind to the marker sequences according to the invention and consequently can be selectively removed from the body fluid.
  • the examples are performed using the UNIarray technology platform based on quantitative analysis of autoantibody profiles in breast cancer patients' serum. This is intended to systematically breast cancer-associated antigens and breast cancer-associated autoantigens (biomarkers)
  • these candidates will be selected for breast cancer-specific marker sequences on serum samples from 100 breast cancer patients and 100 benign women
  • Example 3 The selection of particularly significant biomarkers (breast cancer-specific marker sequences) is carried out by means of
  • the candidates for breast cancer specific marker sequences are evaluated as discriminating between different subjects (e.g., healthy / unhealthy) / patient groups (e.g., low / high risk of metastasis) / cohorts (e.g., particular history).
  • the marker sequence candidates are applied to a protein array and validated.
  • the data analysis is carried out via statistical analyzes, such as threshold value analysis, Support Vector Machine Alogrithm (SVM).
  • SVM Support Vector Machine Alogrithm
  • the sample consumption for validation is only 50 ⁇ / sample.
  • cohorts of category I and II will be selected in this way.
  • the resulting protein array is specific for breast cancer.
  • This protein array includes one or more breast cancer-specific marker sequences and detects breast cancer-associated
  • Anti-estrogen therapy adjuvant chemotherapy or adjuvant aromatase inhibitor therapy.
  • Corresponding protein arrays are being developed for diagnosis, predicting the course of therapy, and predicting metastasis.
  • results of the autoantibody analysis are compared with the golden standard of diagnosis and the identified marker sequences are validated (breast cancer specific marker sequences, marker sequences for breast cancer). The results will then be compared with other clinical
  • a particular autoantibody profile or signal of the protein array is correlated with the response of breast cancer to a particular therapy.
  • changes in the autoantibody profile are validated, including with regard to various treatment options (continuous-time modeling).
  • Example 6 In the development of a protein array for the prediction of metastasis formation, breast cancer specific
  • Metastasis are suitable. By comparing
  • Bioinformatic analyzes can be performed as part of the identification and validation of breast cancer specific marker sequences. For each serum can do so by means of
  • Antigens are measured. These data are used to rank the spotted antigens for their ability to differentiate between healthy and diseased sera.
  • Evaluation can be performed on normalized intensity data using the non-parametric Mann-Whitney test.
  • an internal standard is used that is spotted on each protein array. Since a p-value is calculated for each antigen, methods for correcting the multiple testing are used. As a very conservative approach a Bonferroni correction is performed and in addition the less restrictive False Discovery Rate (FDR) according to Benjamini & Hochberg is calculated.
  • FDR False Discovery Rate
  • the data are used to classify the sera.
  • different multivariate methods are used. These are methods from the statistical
  • Threshold method which is suitable for both classification and visual representation of the data.
  • the erfindungsgermä call sequences are listed in the attached sequence listing.
  • the clone sequences (cDNA) SEQ ID no. 1-491, the RNA sequences SEQ ID. No. 492-982 and the protein sequences SEQ ID No. 983 - 1473).
  • RNA breast cancer specific marker sequences
  • mitochondrial isoform 2 precursor [Homo sapiens]
  • ID-1 isoform b [Homo sapiens]
  • histone deacetylase 7 isoform a [Homo sapiens]
  • Phosphodiesterase 4 isoform 1 [Homo sapiens]
  • modulator 2 isoform 2 [Homo sapiens] 612 gi 140018634 NM_015440.3 monofunctional C-tetrahydrofolate synthase, mitochondrial isoform 2 precursor [Homo sapiens]
  • RNA-binding protein 14 isoform
  • Chemotaxis regulator precursor [Homo sapiens]
  • mitochondrial isoform Ib precursor [Homo sapiens]
  • GIPC1 isoform 2 [Homo sapiens]
  • adenosylhomocysteinase 2 isoform a [Homo sapiens]
  • subunit 5 isoform b [Homo sapiens]
  • initiation factor 2 subunit 2 [Homo sapiens] 719 gi 1237649014 NM_006824.2 probable rRNA processing
  • RNA-binding protein 10 isoform
  • initiation factor 3 subunit M [Homo sapiens] 732 gi 1197100772 NM_020320.3 probable arginyl tRNA
  • member 39 isoform a [Homo sapiens]
  • beta isoform 1 [Homo sapiens]
  • subfamily D member 3 isoform 1 [Homo sapiens]

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Abstract

The present invention relates to a method for identifying marker sequences for breast cancer, to the marker sequences identified with the aid of said method and the diagnostic use thereof, and to diagnostic devices containing marker sequences for breast cancer, in particular an arrangement and a protein array and the use thereof. The invention further relates to methods using these marker sequences for screening potential active substances for the treatment and prevention of breast cancer.

Description

MarkerSequenzen für Brustkrebs und deren Verwendung Marker sequences for breast cancer and their use
Beschreibung description
Die vorliegende Erfindung betrifft ein Verfahren zur The present invention relates to a method for
Identifizierung von Markersequenzen für Brustkrebs, die mit Hilfe dieses Verfahrens identifizierten Markersequenzen und deren diagnostische Verwendung, diagnostische Vorrichtungen enthaltend Markersequenzen für Brustkrebs, insbesondere eine Anordnung und einen Proteinarray sowie deren Verwendung. Identification of marker sequences for breast cancer, the marker sequences identified by this method and their diagnostic use, diagnostic devices containing marker sequences for breast cancer, in particular an assembly and a protein array and their use.
Ferner betrifft die Erfindung Verfahren zum Screenen von potentiellen Wirkstoffen zur Behandlung und Prävention von Brustkrebs mittels dieser Markersequenzen. Furthermore, the invention relates to methods for screening potential drugs for the treatment and prevention of breast cancer by means of these marker sequences.
Proteinarrays gewinnen eine zunehmende industrielle Bedeutung in der Analytik und Diagnostik sowie in der Pharmaentwicklung . Proteinarrays haben sich als Screeninginstrumente etabliert. Protein arrays are gaining increasing industrial importance in analytics and diagnostics as well as in pharmaceutical development. Protein arrays have become established as screening tools.
Hierbei wird die schnelle und hochparallele Detektion einer Vielzahl spezifisch bindender Analysemoleküle in einem Here, the fast and highly parallel detection of a variety of specific binding analysis molecules in one
einzigen Experiment ermöglicht. Zur Herstellung von single experiment allows. For production of
Proteinarrays ist es erforderlich, die benötigten Proteine zur Verfügung zu haben. Hierzu haben sich insbesondere Protein- Expressionsbibliotheken etabliert. Die Hochdurchsat z- Klonierung von definierten offenen Leserahmen ist eine Protein arrays make it necessary to have the required proteins available. In particular, protein expression libraries have been established for this purpose. High throughput z cloning of defined open reading frames is one
Möglichkeit (Heyman, J.A., Cornthwaite, J., Foncerrada, L., Gilmore, J.R., Gontang, E., Hartman, K.J., Hernandez, C.L., Hood, R., Hull, H.M., Lee, W.Y., Marcil, R., Marsh, E.J., Mudd, K.M., Patino, M.J., Purcell, T.J., Rowland, J.J., Possibility (Heyman, JA, Cornthwaite, J., Foncerrada, L., Gilmore, JR, Gontang, E., Hartman, KJ, Hernandez, CL, Hood, R., Hull, HM, Lee, WY, Marcil, R. , Marsh, EJ, Mudd, KM, Patino, MJ, Purcell, TJ, Rowland, JJ,
Sindici, M.L. and Hoeffler, J.P. (1999) Genome-scale cloning and expression of individual open reading frames using Sindici, M.L. and Hoeffler, J.P. (1999) Genome-scale cloning and expression of individual open reading frames using
topoisomerase I-mediated ligation. Genome Res, 9, 383-392; topoisomerase I-mediated ligation. Genome Res, 9, 383-392;
Kersten, B., Feilner, T . , Kramer, A., Wehrmeyer, S., Possling, A., Witt, I., Zanor, M.I., Stracke, R., Lueking, A., Kreut zberger, J., Lehrach, H. and Cahill, D.J. (2003) Kersten, B., Feilner, T. , Kramer, A., Wehrmeyer, S., Possling, A., Witt, I., Zanor, MI, Stracke, R., Lueking, A., Kreut Zberger, J., Lehrach, H. and Cahill, DJ (2003)
Generation of Arabidopsis protein chip for antibody and serum Screening. Plant Molecular Biology, 52, 999-1010; Reboul, J., Vaglio, P., Rual, J.F., Lamesch, P., Martinez, M., Armstrong,Generation of Arabidopsis protein chip for antibody and serum screening. Plant Molecular Biology, 52, 999-1010; Reboul, J., Vaglio, P., Rual, J. F., Lamesch, P., Martinez, M., Armstrong,
C. M., Li, S., Jacotot, L., Bertin, . , Janky, R., Moore, T., Hudson, J.R., Jr . , Hartley, J.L., Brasch, M.A., Vandenhaute, J., Boulton, S., Endress, G.A., Jenna, S., Chevet, E., C.M., Li, S., Jacotot, L., Bertin. , Janky, R., Moore, T., Hudson, J.R., Jr. Hartley, J.L., Brasch, M.A., Vandenhaute, J., Boulton, S., Endress, G.A., Jenna, S., Chevet, E.,
Papasotiropoulos , V., Tolias, P.P., Ptacek, J., Snyder, M., Huang, R., Chance, M.R., Lee, H., Doucette-Stamm, L., Hill,Papasotiropoulos, V., Tolias, P.P., Ptacek, J., Snyder, M., Huang, R., Chance, M.R., Lee, H., Doucette strain, L., Hill,
D. E. and Vidal, M. (2003) C. elegans ORFeome version 1.1: D.E. and Vidal, M. (2003) C. elegans ORFeome version 1.1:
experimental verification of the genome annotation and experimental verification of the genome annotation and
resource for proteome-scale protein expression. Nat Genet, 34, 35-41.; Walhout, A.J., Temple, G.F., Brasch, M.A., Hartley, J.L., Lorson, M.A., van den Heuvel, S. and Vidal, M. (2000)resource for proteome-scale protein expression. Nat Genet, 34, 35-41; Walhout, A.J., Temple, G.F., Brasch, M.A., Hartley, J.L., Lorson, M.A., van den Heuvel, S. and Vidal, M. (2000)
GATEWAY recombinational cloning: application to the cloning of large numbers of open reading frames or ORFeomes. Methods Enzymol, 328, 575-592). Allerdings hängt ein solcher Ansatz stark mit dem Fortschritt der Genom-Sequenzierungspro ekte und der Annotierung dieser Gensequenzen zusammen. Darüber hinaus ist die Bestimmung der exprimierten Sequenz aufgrund GATEWAY recombinational cloning: application to the cloning of large numbers of open reading frames or ORFeems. Methods Enzymol, 328, 575-592). However, such an approach is strongly related to the progress of the genome sequencing proce- dures and the annotation of these gene sequences. In addition, the determination of the expressed sequence is due
differenzieller Spleißvorgänge nicht immer eindeutig. differential splicing is not always clear.
Dieses Problem kann durch die Anwendung von cDNA- Expressionsbibliotheken umgangen werden (Büssow, K., Cahill, D., Nietfeld, W., Bancroft, D., Scherzinger, E., Lehrach, H. and Walter, G. (1998) A method for global protein expression and antibody Screening on high-density filters of an arrayed cDNA library. Nucleic Acids Research, 26, 5007-5008; Büssow, K., Nordhoff, E., Lübbert, C, Lehrach, H. and Walter, G. This problem can be circumvented by the use of cDNA expression libraries (Büssow, K., Cahill, D., Nietfeld, W., Bancroft, D., Scherzinger, E., Lehrach, H. and Walter, G. (1998). Nucleic Acids Research, 26, 5007-5008, Büssow, K., Nordhoff, E., Lübbert, C, Lehrach, H. and Walter , G.
(2000) A human cDNA library for high-throughput protein expression Screening. Genomics, 65, 1-8; Holz, C, Lueking, A., Bovekamp, L., Gut ähr, C., Bolotina, N., Lehrach, H. and Cahill, D.J. (2001) A human cDNA expression library in yeast enriched for open reading frames. Genome Res, 11, 1730-1735; Lueking, A., Holz, C., Gotthold, C., Lehrach, H. and Cahill, D. (2000) A System for dual protein expression in Pichia pastoris and Escherichia coli, Protein Expr . Purif., 20, 372- 378) . Hierbei wird die cDNA eines bestimmten Gewebes in einen bakteriellen oder einen eukaryotischen Expressionsvektor, wie z.B. Hefe, einkloniert. Die für die Expression verwendeten Vektoren zeichnen sich im Allgemeinen dadurch aus, dass sie induzierbare Promotoren tragen, mit denen sich der Zeitpunkt der Proteinexpression steuern lässt. Darüber hinaus weisen Expressionsvektoren Sequenzen für so genannte (2000) A human cDNA library for high-throughput protein expression screening. Genomics, 65, 1-8; Wood, C, Lueking, A., Bovekamp, L., Guther, C., Bolotina, N., Lehrach, H. and Cahill, DJ (2001) A human cDNA expression library in yeast enriched for open reading frames. Genome Res, 11, 1730-1735; Lueking, A., Holz, C., Gotthold, C., Lehrach, H. and Cahill, D. (2000) A system for dual protein expression in Pichia pastoris and Escherichia coli, Protein Expr. Purif., 20, 372-378). Here, the cDNA of a particular tissue in a bacterial or a eukaryotic expression vector, such as yeast, is cloned. The vectors used for the expression are generally characterized by the fact that they carry inducible promoters, with which the timing of protein expression can be controlled. In addition, expression vectors have sequences for so-called
Affinitätsepitope oder -proteine auf, die zum einen den spezifischen Nachweis der rekombinanten Fusions-Proteine mittels eines gegen das Affinitätsepitop gerichteten Affinity epitopes or proteins, on the one hand for the specific detection of the recombinant fusion proteins by means of a directed against the affinity epitope
Antikörpers erlauben, zum anderen wird die spezifische Antibody, on the other hand becomes the specific one
Aufreinigung über Affinitätschromatographie (IMAC) ermöglicht. Purification via affinity chromatography (IMAC) allows.
Beispielsweise wurden die Genprodukte einer cDNA- Expressionsbibliothek aus humanem fötalem Hirngewebe in dem bakteriellen Expressionssystem Escherichia coli im Hochdichte- Format auf einer Membran angeordnet und konnten erfolgreich mit unterschiedlichen Antikörpern gescreent werden. Es konnte gezeigt werden, dass der Anteil an Volllänge-Proteinen bei mindestens 66% liegt. Die rekombinanten Proteine aus For example, the gene products of a cDNA expression library of human fetal brain tissue in the bacterial expression system Escherichia coli in high density format were placed on a membrane and successfully screened with different antibodies. It could be shown that the proportion of full-length proteins is at least 66%. The recombinant proteins out
Expressionsbibliotheken konnten darüber hinaus im In addition, expression libraries have been published in
Hochdurchsatz exprimiert und aufgereinigt werden (Braun P., Hu, Y., Shen, B., Halleck, A., Koundinya, M., Harlow, E. and LaBaer, J. (2002) Proteome-scale purification of human High throughput can be expressed and purified (Braun P., Hu, Y., Shen, B., Halleck, A., Koundinya, M., Harlow, E. and LaBaer, J. (2002) Proteome-scale purification of human
proteins from bacteria. Proc Natl Acad Sei U S A, 99, 2654- 2659; Büssow (2000) supra; Lueking, A., Horn, M., Eickhoff, H., Büssow, K., Lehrach, H. and Walter, G. (1999) Protein microarrays for gene expression and antibody Screening. proteins from bacteria. Proc Natl Acad. USA, 99, 2654-2659; Büssow (2000) supra; Lueking, A., Horn, M., Eickhoff, H., Büssow, K., Lehrach, H. and Walter, G. (1999) Protein microarrays for gene expression and antibody screening.
Analytical Biochemistry, 270, 103-111). Solche Proteinarrays auf der Basis von cDNA-Expressionsbibliotheken sind Analytical Biochemistry, 270, 103-111). Such protein arrays based on cDNA expression libraries are
insbesondere Gegenstand der WO 99/57311 und WO 99/57312. in particular the subject matter of WO 99/57311 and WO 99/57312.
Ferner sind neben Antigen-präsentierenden Proteinarrays ebenfalls Antikörper-präsentierende Anordnungen beschrieben (Lal et al (2002) Antibody arrays : An embryonic but rapidly growing technology, DDT, 7, 143-149; Kusnezow et al . (2003), Antibody microarrays: An evaluation of production parameters, Proteomics, 3, 254-264). Further, in addition to antigen-presenting protein arrays, antibody-presenting arrays are also described (Lal et al (2002) Antibody arrays: An embryonic but growing technology, DDT, 7, 143-149, Kusnezow et al., (2003) Antibody microarrays: An evaluation of production parameters, Proteomics, 3, 254-264).
Brustkrebs (Mammakarzinom) ist der häufigste bösartige Tumor der Brustdrüse des Menschen. Er kommt hauptsächlich bei Frauen vor; nur etwa jede hundertste dieser Krebserkrankungen tritt bei Männern auf. In den westlichen Staaten ist Brustkrebs die häufigste Krebsart bei Frauen und an Brustkrebs sterben mehr Frauen, als an einer anderen Krebserkrankung. Die meisten Erkrankungen treten sporadisch (zufällig) auf, es gibt aber sowohl erbliche als auch erworbene Risikofaktoren. Zahlreiche nationale und internationale Programme zur Früherkennung und zur strukturierten Behandlung sollen die Sterblichkeit senken. Breast cancer (breast cancer) is the most common malignant tumor of the human mammary gland. He occurs mainly in women; Only about one hundred of these cancers occur in men. Breast cancer is the most common cancer in women in the Western world and more women die from breast cancer than from another cancer. Most diseases occur sporadically (by chance), but there are both inherited and acquired risk factors. Numerous national and international programs for early detection and structured treatment aim to reduce mortality.
Etwa 80 bis 90 % aller Geschwulste in der weiblichen Brust werden von den Frauen selbst zufällig entdeckt. Diese tast- und sichtbaren Tumoren sind bei ihrer Entdeckung oft schon relativ groß und sind deshalb meist mit einer schlechten About 80 to 90% of all tumors in the female breast are discovered by chance by the women themselves. These palpable and visible tumors are often relatively large when they are discovered and are therefore usually associated with a bad one
Prognose verbunden. Durch konsequente Früherkennung kleinerer, nicht tastbarer Tumoren könnte die Sterblichkeit deutlich gesenkt werden. Zur Früherkennung dienen Programme zur  Forecast connected. Consistent early detection of smaller, non-palpable tumors could significantly reduce mortality. For early detection programs are used for
systematischen Selbstuntersuchung, der Tastuntersuchung durch den Arzt und die Screening-Mammographie mit Hilfe von Bildgebenden Verfahren sowie die Biopsie. systematic self-examination, tactile examination by the doctor and screening mammography with the help of Imaging procedures as well as biopsy.
Bei Brustkrebs ist eine frühzeitige Diagnose für den weiteren Krankheitsverlauf und die Prognose entscheidend. Obwohl zahlreiche Tumormarker mit Brustkrebs assoziiert sind, sind diese nicht zur Früherkennung geeignet, da sie eine zu geringe Spezifität aufweisen. Sie werden vorwiegend zur Überwachung des Krankheitsverlaufs bzw. des Ansprechens auf die Therapie verwendet . In breast cancer, early diagnosis is crucial for the further course of disease and prognosis. Although many tumor markers are associated with breast cancer, they are not suitable for early diagnosis because of their low specificity. They are mainly used to monitor disease progression or response to therapy.
US 2003/198972 AI offenbart die Identifizierung und Verwendung von Gen Expressionsmustern, die mit verschiedenen Stadien von Brustkrebs assoziiert sind. Die Expressionsmuster werden dabei durch vergleichende Analyse der Genexpression in Gesunden bzw. Patientinnen mit gutartigen Veränderungen und Brustkrebs US 2003/198972 Al discloses the identification and use of gene expression patterns associated with various stages of breast cancer. The expression patterns are analyzed by comparative analysis of gene expression in healthy individuals or patients with benign changes and breast cancer
Patientinnen erhalten. In diesen Studien wird die Probe von den Patientinnen durch nicht-invasives Spülen des Milchgangs entnommen, mikroskopisch untersucht und entartete Zellen werden aus der Probe geerntet. Aus diesen Zellen wird RNA extrahiert, amplifiziert , markiert und diese dann mit Patients received. In these studies, the sample is taken from the patients by non-invasive rinsing of the milk duct, examined microscopically and degenerate cells are harvested from the sample. From these cells, RNA is extracted, amplified, labeled and then with
Mikroarrays, die mit Polynukleotiden bestückt sind, in Kontakt gebracht. Das Intensitätsmuster wird analysiert und ermöglicht eine Zuordung zu verschiedenen Stadien von Brustkrebs. US 2003/198972 AI nennt in diesem Zusammenhang einzelne Gene, deren Expressionsmuster im Zusammenhang mit Brustkrebs Microarrays, which are equipped with polynucleotides, brought into contact. The intensity pattern is analyzed and allows assignment to different stages of breast cancer. US 2003/198972 AI mentions in this context individual genes whose expression pattern in connection with breast cancer
verändert ist. US 2003/198972 offenbart aber keine neuen is changed. However, US 2003/198972 does not disclose new ones
Markersequenzen zum Nachweis dieser Gene. Marker sequences for the detection of these genes.
Karen S. Anderson et al . (Journal of Proteom Research (2011) Bd. 10, Nr. 1, Seiten 85 - 96) offenbart den Nachweis von Autoantikörpern gegen Tumor-assoziierte Proteine mit Hilfe von Protein Mikroarrays und die Anwendung zur Früherkennung von invasivem Brustkrebs. Die dabei verwendeten Protein Mikroarrays werden dadurch hergestellt, dass full-length cDNAs, die für potentielle Tumor-assoziierte Antigene Karen S. Anderson et al. (Journal of Proteom Research (2011) Vol. 10, No. 1, pages 85-96) discloses the detection of autoantibodies against tumor-associated proteins by means of protein microarrays and the application for the early detection of invasive breast cancer. The protein used Microarrays are made by using full-length cDNAs encoding potential tumor-associated antigens
kodieren, auf den Träger geprintet, exprimiert und dann mit den Seren von Brustkrebs Patientinnen und Kontrollpersonen, nämlich Gesunden und solchen mit benignen Brusterkrankungen, vergleichend getestet werden. encoded, printed on the support, expressed and then compared with the sera of breast cancer patients and controls, namely healthy and those with benign breast disease, to be tested comparatively.
US 2012/021887 offenbart die Verwendung von Anordnungen und Protein Mikroarrays mit Markersequenzen für Brustkrebs zum Nachweis von Brustkrebs-spezifischen Autoantikörpern . Es besteht aber weiterhin ein Bedürfnis an US 2012/021887 discloses the use of arrays and protein microarrays with marker sequences for breast cancer for the detection of breast cancer-specific autoantibodies. But there is still a need for
indikationsspezifischen diagnostischen Vorrichtungen und indication specific diagnostic devices and
Verfahren für Brustkrebs, insbesondere zur Früherkennung von Brustkrebs, zur Unterscheidung von Brustkrebs und benignen Veränderungen der Brust und zur Vorhersage des Risikos der Metastasenbildung. Es ist die Aufgabe der vorliegenden Methods for breast cancer, in particular for the early detection of breast cancer, for the differentiation of breast cancer and benign changes in the breast and for the prediction of the risk of metastasis. It is the task of the present
Erfindung verbesserte Mittel zur Früherkennung und Invention improved means for early detection and
Therapiesteuerung bei Brustkrebs bereit zu stellen. Provide therapy control in breast cancer.
Gegenstand der Erfindung ist ein Verfahren zur Identifizierung von Markersequenzen für Brustkrebs dadurch gekennzeichnet, dass a. Markersequenz-Kandidaten für Brustkrebs dadurch The invention relates to a method for identifying marker sequences for breast cancer, characterized in that a. Marker sequence candidates for breast cancer by
identifiziert werden, dass ein Träger, auf dem mindestens 1.000 unterschiedliche Proteine immobilisiert sind, mit einer Serumprobe einer Patientin mit Brustkrebs in Kontakt gebracht wird und Proteine identifiziert werden, die mit dem Serum eine Wechselwirkung zeigen (Markersequenz-Kandidaten) , und b. die Wechselwirkung von einem oder mehreren Markersequenz- Kandidaten aus a. mit dem Serum von Patientinnen mit identifying a carrier on which at least 1,000 different proteins are immobilized being contacted with a serum sample from a breast cancer patient and identifying proteins that interact with the serum (marker sequence candidates), and b. the interaction of one or more marker sequence candidates from a. with the serum of patients with
Brustkrebs bestimmt wird im Vergleich zu der Wechselwirkung des / der Markersequenz-Kandidaten aus a. mit dem Serum von Patientinnen mit benignen Veränderungen und der Wechselwirkung des / der Markersequenz-Kandidaten aus a. mit dem Serum von gesunden Kontrollpersonen, und c. Markersequenzen dadurch identifiziert werden, dass sie mit dem Serum von Patientinnen mit Brustkrebs eine andere Breast cancer is determined as compared to the interaction of the marker sequence candidate from a. with the serum of patients with benign alterations and the interaction of the marker sequence candidate from a. with serum from healthy controls, and c. Marker sequences are identified by being different with the serum from breast cancer patients
Wechselwirkung zeigen als mit dem Serum von Patientinnen mit benignen Veränderungen und dem Serum von gesunden Interaction show as with the serum of patients with benign changes and the serum of healthy
Kontrollpersonen . In einer Ausführungsform des Verfahrens sind auf dem Träger gemäß a. gleichzeitig mindestens 5.000, vorzugsweis mindestens 10.000 unterschiedliche Proteine gleichzeitig immobilisiert. Control persons. In one embodiment of the method, on the support according to a. simultaneously at least 5,000, preferably at least 10,000 different proteins immobilized simultaneously.
Beispielsweise erfolgt dabei die vergleichende Auswertung der Daten der Wechselwirkung aus b. mittels statistischer Analyse, z.B. wie in den Beispielen beschrieben. For example, the comparative evaluation of the data of the interaction from b. by statistical analysis, e.g. as described in the examples.
In einer besonders bevorzugten Ausführungsform des Verfahrens werden Markersequenzen für Brustkrebs identifiziert, die spezifisch sind für Brustkrebs mit einem hohen Risiko der Metastasenbildung . Mit Hilfe des erfindungsgemäßen Verfahrens können In a particularly preferred embodiment of the method, marker sequences for breast cancer are identified which are specific for breast cancer with a high risk of metastasis. With the aid of the method according to the invention can
MarkerSequenzen für Brustkrebs identifiziert werden, die hochspezifisch sind. Markersequenzen, die mit diesem Verfahren gefunden werden, ermöglichen zum Einen die frühzeitige  Marker sequences are identified for breast cancer that are highly specific. Marker sequences that are found with this method, on the one hand enable the early
Erkennung von Brustkrebs z.B. von dessen Vorstufen und zum Anderen die Unterscheidung von Brustkrebs bzw. dessen Detection of breast cancer e.g. of its precursors and on the other hand, the distinction of breast cancer or its
Vorstufen von benignen Veränderungen. Dadurch ist eine Precursors of benign changes. This is one
frühzeitige Diagnose und ggf. eine gezielte Behandlung sowie eine deutlich verbesserte Prognose möglich. Darüber hinaus werden in die Auswertung weitere Patientendaten einbezogen, wie z.B. eine bestimmte Vorgeschichte, Lebensweise und Early diagnosis and possibly targeted treatment and a significantly improved prognosis possible. In addition, further patient data are included in the evaluation, such as a certain history, lifestyle and
insbesondere das Risiko der Metastasenbildung. Auf diese Weise können mit dem erfindungsgemäßen Verfahren Markersequenzen für Brustkrebs identifiziert werden, die bereits im Frühstadium eine Prognose bezüglich des Verlaufs und/oder des Risikos der Metastasenbildung ermöglichen. Die Prognose bezüglich des Risikos der Metastasenbildung ermöglicht auch eine verbesserte Therapie und eine gezielte Überwachung der Patienten im especially the risk of metastasis. In this way, marker sequences for breast cancer can be identified with the method according to the invention, which already at an early stage make it possible to predict the course and / or the risk of metastasis formation. Predicting the risk of metastasis also allows for improved therapy and targeted patient monitoring
Hinblick auf Metastasierung. Im Gegensatz zu den im Stand der Technik von Karen S. Anderson et al . (Supra) beschriebenen Experimenten, werden mit Hilfe des erfindungsgemäßen Verfahrens Markersequenzen With regard to metastasis. In contrast to the prior art of Karen S. Anderson et al. (Supra) described experiments, using the method according to the invention marker sequences
identifiziert, die spezifischer sind, z.B. weil sie nicht nur die Diskriminierung von Brustkrebs von gutartigen which are more specific, e.g. because they are not only the discrimination of benign breast cancer
Veränderungen des Gewebes (benigne Veränderung) ermöglichen, sondern darüber hinaus eine Aussage bzgl. der Prognose Changes in the tissue (benign change) allow, but also a statement regarding the prognosis
beispielsweise im Hinblick auf das Risiko der Metasasierung und dadurch die gezielte Überwachung und Therapie dieser For example, with regard to the risk of metastases and thus the targeted monitoring and therapy of these
Patienten ermöglichen. Die erfindungsgemäßen Markersequenzen sind zur Analyse von Körperflüssigkeiten wie z.B. Serum besonders geeignet. Dadurch ist eine schnelle und Enable patients. The marker sequences of the invention are useful for the analysis of body fluids, e.g. Serum particularly suitable. This is a fast and easy way
kostengünstige Verwendung bzw. Anwendung der erfindungsgemäßen Markersequenzen möglich. cost-effective use or application of the marker sequences of the invention possible.
Gegenstand der Erfindung sind auch die mit dem The invention also relates to the
erfindungsgemäßen Verfahren identifizierten Markersequenzen für Brustkrebs. Gegenstand der Erfindung sind Markersequenzen für Brustkrebs erhältlich durch ein erfindungsgemäßes methods of the invention identified marker sequences for breast cancer. The invention provides marker sequences for breast cancer obtainable by an inventive
Verfahren und ausgewählt aus den Sequenzen umfassend SEQ ID o. 1 - 1473 und Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise 95 % der Länge der Sequenzen SEQ ID No . 1 - 1473 und Homologen von SEQ ID No . 1- 1473 und deren Teilsequenzen mit einer Identität von mindestens 95%, vorzugsweise 98 % oder mehr zu den entsprechenden A method and selected from the sequences comprising SEQ ID o. 1-1473 and partial sequences of SEQ ID No. 1 to 1473 with at least 90%, preferably 95% of the length of the sequences SEQ ID No. 1 - 1473 and homologs of SEQ ID No. 1-1473 and theirs Partial sequences with an identity of at least 95%, preferably 98% or more, to the corresponding ones
Nukleinsäure- und/oder Proteinsequenzen und Sequenzen kodiert durch SEQ ID o. 1 - 491, Teilsequenzen davon sowie deren Homologe. Nucleic acid and / or protein sequences and sequences encoded by SEQ ID o. 1-491, partial sequences thereof and their homologs.
Gegenstand der Erfindung ist auch eine Anordnung umfassend eine oder mehrere erfindungsgemäße Markersequenzen. The invention also provides an arrangement comprising one or more marker sequences according to the invention.
Gegenstand der Erfindung ist auch ein Proteinarray umfassend eine oder mehrere erfindungsgemäße Markersequenzen. Gegenstand der Erfindung ist auch ein Diagnostikum umfassend eine oder mehrere erfindungsgemäße Markersequenzen und gegebenenfalls weitere Zusatz- und/oder Hilfsstoffe. The invention also provides a protein array comprising one or more marker sequences according to the invention. The invention also provides a diagnostic agent comprising one or more marker sequences according to the invention and optionally further additives and / or auxiliaries.
Gegenstand der Erfindung ist auch ein Test Kit umfassend eine oder mehrere erfindungsgemäße Markersequenzen und The invention also provides a test kit comprising one or more marker sequences according to the invention and
gegebenenfalls weitere Zusatz- und/oder Hilfsstoffe. optionally further additives and / or auxiliaries.
Gegenstand der Erfindung ist auch eine erfindungsgemäße The invention is also an inventive
Anordnung dadurch gekennzeichnet, dass 2 oder 3, vorzugsweise 4 oder 5, besonders bevorzugt 7 oder 8 oder mehr Arrangement characterized in that 2 or 3, preferably 4 or 5, more preferably 7 or 8 or more
unterschiedliche Markersequenzen für Brustkrebs gleichzeitig verwendet werden. different marker sequences for breast cancer are used simultaneously.
Gegenstand der Erfindung ist auch ein erfindungsgemäßer The invention also provides an inventive
Proteinarray dadurch gekennzeichnet, dass 2 oder 3, Protein array characterized in that 2 or 3,
vorzugsweise 4 oder 5, besonders bevorzugt 7 oder 8 oder mehr unterschiedliche Markersequenzen für Brustkrebs gleichzeitig verwendet werden. preferably 4 or 5, more preferably 7 or 8 or more different marker sequences for breast cancer are used simultaneously.
Gegenstand der Erfindung ist auch ein erfindungsgemäßes Diagnostikum dadurch gekennzeichnet, dass 2 oder 3, The subject of the invention is also a diagnostic agent according to the invention, characterized in that 2 or 3,
vorzugsweise 4 oder 5, besonders bevorzugt 7 oder 8 oder mehr unterschiedliche Markersequenzen für Brustkrebs gleichzeitig verwendet werden. preferably 4 or 5, more preferably 7 or 8 or more different marker sequences for breast cancer are used simultaneously.
Gegenstand der Erfindung ist auch ein erfindungsgemäßer Test Kit dadurch gekennzeichnet, dass 2 oder 3, vorzugsweise 4 oder 5, besonders bevorzugt 7 oder 8 oder mehr unterschiedlicheThe invention also provides a test kit according to the invention characterized in that 2 or 3, preferably 4 or 5, more preferably 7 or 8 or more different
MarkerSequenzen für Brustkrebs gleichzeitig verwendet werden. Marker sequences for breast cancer are used simultaneously.
Gegenstand der Erfindung ist auch die Verwendung einer oder mehrerer erfindungsgemäßer Markersequenzen, einer The invention also provides the use of one or more marker sequences according to the invention, one
erfindungsgemäßen Anordnung, eines erfindungsgemäßen inventive arrangement, an inventive
Proteinarrays , eines erfindungsgemäßen Diagnostikums oder eines erfindungsgemäßen Test Kits zur Früherkennung, Diagnose, Prognose, Therapiesteuerung und/oder Nachsorge bei Brustkrebs. Protein arrays, a diagnostic agent according to the invention or a test kit according to the invention for early detection, diagnosis, prognosis, therapy control and / or aftercare in breast cancer.
Gegenstand der Erfindung ist auch die Verwendung einer oder mehrerer erfindungsgemäßer Markersequenzen, einer The invention also provides the use of one or more marker sequences according to the invention, one
erfindungsgemäßen Anordnung, eines erfindungsgemäßen inventive arrangement, an inventive
Proteinarrays, eines erfindungsgemäßen Diagnostikums oder eines erfindungsgemäßen Test Kits zur Unterscheidung von  Protein arrays, a diagnostic agent according to the invention or a test kit according to the invention for distinguishing
Brustkrebs von benignen Veränderungen und / oder zur Prognose beispielsweise bzgl. des Risikos der Metastasenbildung. Gegenstand der Erfindung ist auch die Verwendung einer oder mehrerer erfindungsgemäßer Markersequenzen, einer Breast cancer from benign changes and / or prognosis, for example regarding the risk of metastasis. The invention also provides the use of one or more marker sequences according to the invention, one
erfindungsgemäßen Anordnung, eines erfindungsgemäßen inventive arrangement, an inventive
Proteinarrays, eines erfindungsgemäßen Diagnostikums oder eines erfindungsgemäßen Test Kits zur individualisierten Protein arrays, a diagnostic agent of the invention or a test kit according to the invention for individualized
Diagnostik und/oder Therapie bei einzelnen Patienten, Diagnosis and / or therapy in individual patients,
Patientengruppen, Kohorten, Bevölkerungsgruppen, Varianten von Brustkrebs, Stadien von Brustkrebs.  Patient groups, cohorts, populations, breast cancer variants, stages of breast cancer.
Gegenstand der Erfindung ist auch die Verwendung einer oder mehrerer erfindungsgemäßer Markersequenzen, einer erfindungsgemäßen Anordnung, eines erfindungsgemäßen Proteinarrays , eines erfindungsgemäßen Diagnostikums oder eines erfindungsgemäßen Test Kits zum Nachweis und/oder zur Bestimmung der Menge von einem oder mehreren Autoantikörpern die mit Brustkrebs assoziiert sind, beispielsweise in The invention also provides the use of one or more marker sequences according to the invention, one A device according to the invention, a protein array according to the invention, a diagnostic agent of the invention or a test kit according to the invention for detecting and / or determining the amount of one or more autoantibodies associated with breast cancer, for example in
Körperflüssigkeiten wie Serum, Gewebe oder Gewebeauszügen des Patienten .  Body fluids such as serum, tissue or tissue extracts of the patient.
Gegenstand der Erfindung ist auch die Verwendung einer oder mehrerer erfindungsgemäßer Markersequenzen, einer The invention also provides the use of one or more marker sequences according to the invention, one
erfindungsgemäßen Anordnung, eines erfindungsgemäßen inventive arrangement, an inventive
Proteinarrays, eines erfindungsgemäßen Diagnostikums oder eines erfindungsgemäßen Test Kits zur Analyse von  Protein arrays, a diagnostic agent of the invention or a test kit according to the invention for the analysis of
Autoantikörperprofilen von Patienten, insbesondere zur Autoantibody profiles of patients, in particular for
qualitativen und/oder quantitativen Analyse von qualitative and / or quantitative analysis of
Autoantikörpern und/oder zur Überwachung von Veränderungen von Autoantikörperprofilen, beispielsweise in Körperflüssigkeiten wie Serum, Gewebe oder Gewebeauszügen des Patienten. Autoantibodies and / or for monitoring changes in autoantibody profiles, for example in body fluids such as serum, tissue or tissue extracts of the patient.
Gegenstand der Erfindung ist auch die Verwendung einer oder mehrerer erfindungsgemäßer Markersequenzen, einer The invention also provides the use of one or more marker sequences according to the invention, one
erfindungsgemäßen Anordnung, eines erfindungsgemäßen inventive arrangement, an inventive
Proteinarrays, eines erfindungsgemäßen Diagnostikums oder eines erfindungsgemäßen Test Kits zum Screenen von Substanzen (Wirkstoffen) für Brustkrebs.  Protein arrays, a diagnostic agent of the invention or a test kit according to the invention for the screening of substances (drugs) for breast cancer.
Gegenstand der Erfindung ist auch ein Target zur Behandlung und / oder Therapie von Brustkrebs, wobei das Target aus den erfindungsgemäßen Markersequenzen SEQ ID No . 1- 1473 und The invention also provides a target for the treatment and / or therapy of breast cancer, wherein the target of the marker sequences of the invention SEQ ID No. 1-1473 and
Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise 95 % der Länge der Sequenzen SEQ ID No. 1 - 1473 und Homologen von SEQ ID No . 1- 1473 und deren Teilsequenzen mit einer Identität von mindestens 95%, vorzugsweise 98 % oder mehr zu den entsprechenden Nukleinsäure- und/oder Partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably 95% of the length of the sequences SEQ ID NO. 1 - 1473 and homologs of SEQ ID No. 1-1473 and their subsequences with an identity of at least 95%, preferably 98% or more to the corresponding nucleic acid and / or
Proteinsequenzen und Sequenzen kodiert durch SEQ ID No. 1 - 491, Teilsequenzen davon sowie deren Homologe ausgewählt wird. Protein sequences and sequences encoded by SEQ ID no. 1 - 491, partial sequences thereof and their homologues are selected.
Gegenstand der Erfindung ist auch ein Verfahren zur The invention also provides a method for
Früherkennung, Diagnose, Prognose, Therapiesteuerung und/oder Nachsorge bei Brustkrebs wobei Early detection, diagnosis, prognosis, therapy control and / or aftercare for breast cancer
a. ) eine oder mehrere Markersequenz (en) ausgewählt aus der Gruppe umfassend die Sequenzen SEQ ID No. 1 - 1473 und a. ) one or more marker sequence (s) selected from the group comprising the sequences SEQ ID NO. 1 - 1473 and
Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise 95 % der Länge der Sequenzen SEQ ID No . 1 - 1473 und Homologen von SEQ ID No . 1- 1473 und deren Teilsequenzen mit einer Identität von mindestens 95%, vorzugsweise 98 % oder mehr zu den entsprechenden Nukleinsäure- und/oder Partial sequences of SEQ ID No. 1 to 1473 with at least 90%, preferably 95% of the length of the sequences SEQ ID No. 1 - 1473 and homologs of SEQ ID No. 1-1473 and their partial sequences with an identity of at least 95%, preferably 98% or more to the corresponding nucleic acid and / or
Proteinsequenzen und Sequenzen kodiert durch SEQ ID No. 1 - 491, Teilsequenzen davon sowie deren Homologe auf einen Träger aufgebracht wird/werden, Protein sequences and sequences encoded by SEQ ID no. 1 - 491, partial sequences thereof and their homologues are applied to a carrier,
b. ) mit Körperflüssigkeit oder Gewebeauszug eines Patienten in Kontakt gebracht wird/werden und b. ) is brought into contact with body fluid or tissue extract of a patient and / or
c. ) der Nachweis einer Wechselwirkung der Körperflüssigkeit oder des Gewebeauszugs mit der/den Markersequenz (en) für c. ) the detection of an interaction of the body fluid or tissue extract with the marker sequence (s) for
Brustkrebs aus a.) erfolgt.  Breast cancer from a.) Is done.
Die Brustkrebs-spezifischen Markersequenzen SEQ ID No . 1 - 491 wurde hier erstmals beschrieben. Alle diesen Sequenzen ist gemein, dass sie mittels eines Proteinarrays und dem in den Beispielen beschriebenen Verfahren identifiziert wurden. Die Erfindung betrifft deshalb insbesondere auch die Brustkrebs¬ spezifische Markersequenz ausgewählt aus den Sequenzen The breast cancer-specific marker sequences SEQ ID No. 1 - 491 has been described here for the first time. All of these sequences have in common that they have been identified by means of a protein array and the method described in the examples. The invention therefore relates in particular breast cancer-specific markers ¬ sequence selected from the sequences
umfassend SEQ ID No. 1 - 491 und Teilsequenzen von SEQ ID No . 1 - 491 mit mindestens 90 %, vorzugsweise 95 % der Länge der Sequenzen SEQ ID No. 1 - 491 und Homologen von SEQ ID No . 1-comprising SEQ ID no. 1-491 and partial sequences of SEQ ID No. 1-491 with at least 90%, preferably 95% of the length of the sequences SEQ ID NO. 1-491 and homologs of SEQ ID No. 1-
491 und deren Teilsequenzen mit einer Identität von mindestens 95%, vorzugsweise 98 % oder mehr zu den entsprechenden 491 and their subsequences with an identity of at least 95%, preferably 98% or more of the corresponding
Sequenzen und Proteinen/Peptiden kodiert durch die Sequenzen SEQ ID No . 1 - 491, kodiert durch die Teilsequenzen und die Homologen . Im Rahmen diese Erfindung wurde für die Proteine SEQ ID No . 983 bis 1473 und/oder Teilsequenzen dieser Proteine und/oder Proteine kodiert durch Sequenzen SEQ ID No. 1 - 491 und/oder Proteine kodiert durch Sequenzen SEQ ID. No . 492 - 982 Sequences and proteins / peptides encoded by the sequences SEQ ID No. 1-491, encoded by the partial sequences and the homologs. In the context of this invention, the proteins SEQ ID No. 983 to 1473 and / or partial sequences of these proteins and / or proteins encoded by sequences SEQ ID no. 1-491 and / or proteins encoded by sequences SEQ ID. No. 492 - 982
und/oder kodiert durch Teilsequenzen von SEQ ID. No . 1 - 982 erstmals eine Brustkrebs-spezifische Verwendung gefunden und in der erfindungsgemäßen Anordnung, dem erfindungsgemäßen Diagnostikum, dem erfindungsgemäßen Test Kit und dem and / or encoded by partial sequences of SEQ ID. No. 1-982 first found a breast cancer-specific use and in the inventive arrangement, the diagnostic agent according to the invention, the test kit according to the invention and the
erfindungsgemäßen Proteinarray umgesetzt. converted protein array according to the invention.
Die Erfindung stellt damit Markersequenzen und Anordungen von MarkerSequenzen für Brustkrebs zur Verfügung, die Rahmen einer individualisierten Diagnostik und Therapie verwendet werden können, um beispielsweise bei unterschiedlichen Patienten, Patientengruppen, Kohorten, Bevölkerungsgruppen, The invention thus provides marker sequences and arrangements of marker sequences for breast cancer which can be used as part of individualized diagnostics and therapy, for example in the case of different patients, patient groups, cohorts, population groups,
Brustkrebsvarianten, Brustkrebsstadien gezielt und individuell angepasst Brustkrebs zu diagnostizieren und die Therapie zu überwachen . Breast cancer variants, breast cancer stages targeted and customized to diagnose breast cancer and to monitor the therapy.
Die Erfindung betrifft die Verwendung von einer oder mehreren Markersequenzen für Brustkrebs (= Brustkrebs-spezifische The invention relates to the use of one or more marker sequences for breast cancer (= breast cancer-specific
Markersequenz), wobei die Brustkrebs-spezifische (n) Marker sequence), with the breast cancer specific (s)
Markersequenz (en) ausgewählt wird/werden aus den Sequenzen SEQ ID No. 1 - 1473 und Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise mindestens 95 % der Länge von SEQ ID No. 1 - 1473 und Homologen von SEQ ID No . 1 - 1473 und deren Teilsequenzen mit einer Identität von mindestens 95 %, vorzugsweise mindestens 98 % oder mehr zu den entsprechenden Sequenzen und Proteinen/Peptiden kodiert durch die Sequenzen SEQ ID No. 1 - 491, kodiert durch deren Teilsequenzen und Homologen für Brustkrebsdiagnose und Therapie, insbesondere zur Früherkennung von Brustkrebs, zur Diagnose von Brustkrebs, zur Prognose, beispielsweise des Risikos der Marker sequence (s) is / are selected from the sequences SEQ ID NO. 1 - 1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID NO. 1 - 1473 and homologs of SEQ ID No. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more, to the corresponding ones Sequences and proteins / peptides encoded by the sequences SEQ ID no. 1 - 491, encoded by their partial sequences and homologues for breast cancer diagnosis and therapy, in particular for the early detection of breast cancer, for the diagnosis of breast cancer, for the prognosis, for example of the risk of
Metastasenbildung, Therapiesteuerung, beispielsweise  Metastasis, therapy control, for example
Vorhersage und Überwachung des Ansprechens auf ein Predict and monitor the response to a
Arzneimittel oder eine Therapie, Nachsorge. Die Erfindung betrifft insbesondere auch den Nachweis und die Bestimmung der Menge von mindestens zwei verschiedenen Autoantikörpern bei einem Patienten wobei entsprechend mindestens zwei Medicines or a therapy, aftercare. In particular, the invention also relates to the detection and determination of the amount of at least two different autoantibodies in a patient, correspondingly at least two
verschiedene erfindungsgemäße Brustkrebs-spezifische various breast cancer-specific according to the invention
Markersequenzen (als Antigene) verwendet werden. Marker sequences (used as antigens).
Gegenstand der Erfindung ist auch eine erfindungsgemäße The invention is also an inventive
Anordnung von einer oder mehreren Brustkrebs-spezifischenArrangement of one or more breast cancer-specific
MarkerSequenzen auf einem Träger zur Analyse von Brustkrebsassoziierten Autoantikörperprofilen, Früherkennung, Diagnose, Prognose und/oder Therapiesteuerung bei Brustkrebs wobei die Brustkrebs-spezifische (n) Markersequenz (en) ausgewählt Carrier-based marker sequences for the analysis of breast cancer-associated autoantibody profiles, early detection, diagnosis, prognosis and / or therapy control in breast cancer, wherein the breast cancer specific marker sequence (s) is selected
wird/werden aus Gruppe SEQ ID No. 1 bis 1473 und Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise mindestens 95 % der Länge von SEQ ID No. 1 - 1473 und is / are selected from group SEQ ID no. 1 to 1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID NO. 1 - 1473 and
Homologen von SEQ ID No. 1 - 1473 und deren Teilsequenzen mit einer Identität von mindestens 95 %, vorzugsweise mindestens 98 % oder mehr zu den entsprechenden Sequenzen und Homologs of SEQ ID no. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more, to the corresponding sequences and
Proteinen/Peptiden kodiert durch die Sequenzen SEQ ID No. 1 - 491, kodiert durch deren Teilsequenzen und Homologen.  Proteins / peptides encoded by the sequences SEQ ID no. 1 - 491 encoded by their partial sequences and homologs.
Gegenstand der Erfindung ist auch eine erfindungsgemäße The invention is also an inventive
Anordnung oder eine erfindungsgemäße Verwendung von einer oder mehreren Brustkrebs-spezifischen Markersequenz (en) wobei mindestens 2, beispielsweise 3 bis 5 oder 10, vorzugsweise 30 bis 50 oder 50 bis 100 oder mehr Brustkrebs-spezifische Arrangement or use according to the invention of one or more breast cancer-specific marker sequence (s) wherein at least 2, for example 3 to 5 or 10, preferably 30 to 50 or 50 to 100 or more breast cancer-specific
MarkerSequenzen an oder zu einem zu untersuchenden Patienten bestimmt werden. Marker sequences are determined on or to a patient to be examined.
Gegenstand der Erfindung ist auch eine erfindungsgemäße The invention is also an inventive
Verwendung, Anordnung, Proteinarray, Diagnostikum, Test Kit wobei die Brustkrebs-spezifische (n) Markersequenz (en) auf einem festen Träger aufgebracht wird/werden, insbesondere einem Filter, einer Membran, einem bead oder kleinen Plättchen oder Kügelchen, beispielsweise einem magnetischen oder Use, Arrangement, Protein Array, Diagnostic, Test Kit wherein the breast cancer specific marker sequence (s) are / are applied to a solid support, in particular a filter, membrane, bead or small platelet or bead, for example a magnetic or
Fluorophor-markierten Kügelchen, einem Silizium-Wafer , Glas, Metall, Kunststoff, einem Chip, einem massenspektrometrisches Target oder einer Matrix. Fluorophore-labeled beads, a silicon wafer, glass, metal, plastic, a chip, a mass spectrometric target or a matrix.
Ein besondere Ausführungsform betrifft die Verwendung eines Filters als festen Träger. Als Filter ist weiterhin PVDF, Nitrocellulose oder Nylon bevorzugt (z.B. Immobilon P A particular embodiment relates to the use of a filter as a solid support. As a filter, PVDF, nitrocellulose or nylon is further preferred (e.g., Immobilon P
Millipore, Protran Whatman, Hybond N+ Amersham) . Millipore, Protran Whatman, Hybond N + Amersham).
Eine weitere Ausführungsform betrifft eine Another embodiment relates to a
Anordnung/Verwendung, dadurch gekennzeichnet, dass die Arrangement / use, characterized in that the
Brustkrebs-spezifischen Markersequenz (en) als Klon(e) vorliegt / vorliegen. Daher betrifft die Erfindung die Verwendung von Brustkrebs-spezifischen Markersequenzen zur Diagnose von Breast cancer specific marker sequence (s) present as clone (s). Therefore, the invention relates to the use of breast cancer-specific marker sequences for the diagnosis of
Brustkrebs, wobei mindestens eine Brustkrebs-spezifische Breast cancer, being at least one breast cancer-specific
Markersequenz einer DNA, insbesondere cDNA ausgewählt aus der Gruppe SEQ ID No . 1-491 oder RNA ausgewählt aus der Gruppe 492-982 oder einer Teilsequenz oder eines Fragments oder eine homologen Sequenz davon an oder zu einem zu untersuchenden Patienten bestimmt wird. Marker sequence of a DNA, in particular cDNA selected from the group SEQ ID No. 1-491 or RNA selected from the group 492-982 or a partial sequence or a fragment or a homologous sequence thereof is determined on or to a patient to be examined.
Die Bereitstellung von Brustkrebs-spezifischen Markersequenzen (auch erfindungsgemäße Markersequenzen genannt) erlaubt eine sichere Diagnose und Stratifizierung von Patienten mit The provision of breast cancer-specific marker sequences (also called marker sequences according to the invention) permits a safe diagnosis and stratification of patients with
Brustkrebs insbesondere mittels eines Proteinarrays . Breast cancer, in particular by means of a protein array.
Die erfindungsgemäßen Brustkrebs-spezifischen Markersequenzen konnten mittels differentiellem Screenen von Proben und zwar gesunder Probanden mit Patientenproben mit Brustkrebs The breast cancer-specific marker sequences according to the invention were able to be detected by differential screening of samples, namely healthy subjects, with patient samples containing breast cancer
identifiziert werden. Hierbei konnten diese erfindungsgemäßen Markersequenzen erstmals mittels Proteinarrays (siehe be identified. In this case, these marker sequences according to the invention could be detected for the first time by means of protein arrays (see
Beispiele) identifiziert werden. Examples) are identified.
Gegenstand der Erfindung ist auch ein Verfahren zur The invention also provides a method for
Identifizierung von Markersequenzen für Brustkrebs umfassend die Schritte a) Bereitstellung von Sequenzen auf einem Array, b) Identifizierung von Markersequenz Kandidaten für Identification of marker sequences for breast cancer comprising the steps of a) providing sequences on an array, b) identifying marker sequence candidates for
Brustkrebs durch vergleichende Analyse der Signale, die bei Kontakt der Markersequenzen mit Körperflüssigkeit oder Breast cancer by comparative analysis of signals resulting from contact of the marker sequences with body fluid or
Gewebeauszug eines Patienten mit Brustkrebs und Tissue extract of a patient with breast cancer and
Körperflüssigkeit oder Gewebeauszug eines Patienten ohne Body fluid or tissue extract of a patient without
Brustkrebs gemessen werden, c) Charakterisierung der Markersequenz Kandidaten für C) characterization of marker sequence candidates for
Brustkrebs mit Hilfe eines Proteinarrays, d) Auswahl von Markersequenzen für Brustkrebs, die ein unterschiedliches Signal bei Patienten mit Brustkrebs und Patienten ohne Brustkrebs liefern (Brustkrebs-spezifische Markersequenzen) . Der Begriff „Brustkrebs" umfasst eine Gruppe von Erkrankungen, die Vorstufen zu Brustkrebs sein können und deren Etablierung als Brustkrebs, Mammakarzinom (Definition z.B. nach D) Selection of marker sequences for breast cancer, which give a different signal in patients with breast cancer and patients without breast cancer (breast cancer-specific marker sequences). The term "breast cancer" includes a group of diseases that may be precursors to breast cancer and their establishment as breast cancer, breast cancer (as defined, for example, in US Pat
Pschyrembel, de Gruyter, 263. Auflage (2012), Berlin). Brustkrebsvarianten und Brustkrebsstadien sind ebenfalls der Definition nach Pschyrembel zu entnehmen. Pschyrembel, de Gruyter, 263rd Edition (2012), Berlin). Breast cancer variants and breast cancer stages are also defined by Pschyrembel.
In einer weiteren Ausführungsform der Erfindung können die erfindungsgemäßen Markersequenzen ebenfalls mit bekannten Biomarkern für diese Indikation kombiniert, ergänzt oder erweitert werden. Dabei sind jedoch mindestens 50 %, In a further embodiment of the invention, the marker sequences according to the invention can also be combined, supplemented or extended with known biomarkers for this indication. However, at least 50%,
vorzugsweise 60 %, besonders bevorzugt 70 % oder mehr preferably 60%, more preferably 70% or more
erfindungsgemäße Markersequenzen vertreten, beispielsweise in der erfindungsgemäßen Anordnung, dem erfindungsgemäßen represent marker sequences according to the invention, for example in the inventive arrangement, the inventive
Proteinarray, dem erfindungsgemäßen Diagnostikum oder dem erfindungsgemäßen Test Kit. In besonders bevorzugten Protein array, the diagnostic agent according to the invention or the test kit according to the invention. In particularly preferred
Ausführungsformen der Erfindung, insbesondere der Embodiments of the invention, in particular the
erfindungsgemäßen Anordnung, dem erfindungsgemäßen Assay und Proteinarray sowie der erfindungsgemäßen Verwendung sind mindestens 75 %, vorzugsweise 80 % oder 85 %, besonders bevorzugt 90 % oder 95 % erfindungsgemäße Markersequenzen vertreten . The arrangement according to the invention, the assay and protein array according to the invention and the use according to the invention represent at least 75%, preferably 80% or 85%, particularly preferably 90% or 95% of marker sequences according to the invention.
In einer bevorzugten Ausführungsform erfolgt die Bestimmung der Brustkrebs-spezifischen Markersequenzen außerhalb des menschlichen Körpers und die Bestimmung erfolgt in einer ex vivo / in vitro Diagnose. In a preferred embodiment, the determination of the breast cancer-specific marker sequences takes place outside the human body and the determination takes place in an ex vivo / in vitro diagnosis.
Gegenstand der Erfindung ist auch ein Assay oder Proteinarray umfassend eine erfindungsgemäße Anordnung/Verwendung. Die Erfindung betrifft eine diagnostische Vorrichtung und/oder einen Assay, insbesondere einen Proteinarray der für The invention also relates to an assay or protein array comprising an arrangement / use according to the invention. The invention relates to a diagnostic device and / or an assay, in particular a protein array for
Brustkrebs eine Früherkennung, Diagnose, Prognose, Breast cancer early detection, diagnosis, prognosis,
Stratifizierung und/oder Untersuchung erlaubt. Stratification and / or examination allowed.
Die Erfindung betrifft auch die Verwendung einer The invention also relates to the use of a
erfindungsgemäßen Anordnung oder eines erfindungsgemäßen Assays oder Proteinarrays zur Analyse von Autoantikörperprofilen von Patienten, insbesondere zur inventive arrangement or an assay or protein array according to the invention for the analysis of Autoantibody profiles of patients, in particular for
quantitativen Analyse und/oder zur Überwachung von quantitative analysis and / or monitoring of
Veränderungen von Autoantikörperprofilen von Patienten. Changes in autoantibody profiles of patients.
Gegenstand der Erfindung ist auch ein Diagnostikum (Test Kit) zur Früherkennung und/oder Diagnose von Brustkrebs und/oderThe invention also provides a diagnostic (test kit) for the early detection and / or diagnosis of breast cancer and / or
Prognose und/oder Vorhersage des Risikos der Metastasenbildung bei Brustkrebs umfassend eine erfindungsgemäße Anordnung vorzugsweise auf einem Träger oder einen erfindungsgemäßen Assay oder Proteinarray und gegebenenfalls weitere Zusatz- und Hilfsstoffe. Prognosis and / or prediction of the risk of metastasis formation in breast cancer comprising an arrangement according to the invention, preferably on a carrier or an assay or protein array according to the invention and, if appropriate, further additives and auxiliaries.
Gegenstand der Erfindung ist auch ein Diagnostikum (Test Kit) zur Therapieüberwachung und/oder Nachsorge bei Brustkrebs umfassend eine erfindungsgemäße Anordnung oder einen The invention also provides a diagnostic (test kit) for monitoring therapy and / or aftercare in breast cancer comprising an arrangement according to the invention or a
erfindungsgemäßen Assay oder Proteinarray und gegebenenfalls weitere Zusatz- und Hilfsstoffe. inventive assay or protein array and optionally other additives and excipients.
In einer weiteren Ausführungsform der Erfindung betrifft die Erfindung die Verwendung von Brustkrebs-spezifischen In a further embodiment of the invention, the invention relates to the use of breast cancer-specific
Markersequenzen als Diagnostika, wobei mindestens eine Marker sequences as diagnostic agents, wherein at least one
Markersequenz einer cDNA ausgewählt aus der Gruppe SEQ ID No . 1-491 (Klon Sequenzen) oder SEQ ID No . 492-982 (RNA) oder jeweils ein durch SEQ ID No . 1-982 kodiertes Protein oder jeweils eine Teilsequenz oder Fragment davon ist. Marker sequence of a cDNA selected from the group SEQ ID No. 1-491 (clone sequences) or SEQ ID No. 492-982 (RNA) or one each by SEQ ID No. 1-982 is a coded protein or each a partial sequence or fragment thereof.
Gegenstand der Erfindung ist auch ein Verfahren zur The invention also provides a method for
Früherkennung und Diagnose von Brustkrebs wobei Early detection and diagnosis of breast cancer being
a.) eine oder mehrere Brustkrebs-spezifische Markersequenzen ausgewählt aus der Gruppe der Sequenzen SEQ ID No. 1 - 1473 und Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise mindestens 95 % der Länge von SEQ ID No. 1 - 1473 und Homologen von SEQ ID No. 1 - 1473 und deren Teilsequenzen mit einer Identität von mindestens 95 %, vorzugsweise mindestens 98 % oder mehr zu den entsprechenden Sequenzen und Proteinen/Peptiden kodiert durch die Sequenzen SEQ ID o. 1 - 491, kodiert durch deren Teilsequenzen und Homologen auf einem Träger aufgebracht werden und a.) one or more breast cancer-specific marker sequences selected from the group of the sequences SEQ ID NO. 1 - 1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID NO. 1 - 1473 and homologues of SEQ ID no. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more of the corresponding sequences and proteins / peptides encoded by the sequences SEQ ID NO. 1-491, encoded by their partial sequences and homologues are applied to a support and
b.) mit Körperflüssigkeit oder Gewebeauszug eines Patienten in Kontakt gebracht werden und b.) be brought into contact with body fluid or tissue extract of a patient and
c.) der Nachweis einer Wechselwirkung der Körperflüssigkeit oder Gewebeauszug mit den Brustkrebs-spezifischen c.) the detection of an interaction of body fluid or tissue extract with the breast cancer-specific
Markersequenzen aus a.) erfolgt. Eine besondere Ausführungsform der Erfindung betrifft Marker sequences from a.) Is done. A particular embodiment of the invention relates
Verfahren zur Früherkennung und Diagnose von Brustkrebs, wobei die Wechselwirkung nach c.) ein Brustkrebs-assoziiertes  Method for the early detection and diagnosis of breast cancer, wherein the interaction after c.) Is a breast cancer-associated
Autoantikörperprofil des Patienten oder einer Kohorte oder einer Bevölkerungsgruppe oder eines bestimmten Autoantibody profile of the patient or a cohort or a population group or a specific one
Krankheitsverlaufs (Prognose) oder eines bestimmten Disease course (prognosis) or a certain
Ansprechens auf eine Therapie/Arzneimittel abbildet. Response to a therapy / drug images.
In einem Verfahren zur Diagnose und/oder in einem Diagnostikum und/oder einem Test Kit werden ein oder mehrere Brustkrebsspezifische MarkerSequenzen verwendet. In einer bevorzugten Ausführungsform werden mindestens 2, beispielsweise 3, 4, 5,One or more breast cancer specific marker sequences are used in a method of diagnosis and / or in a diagnostic and / or a test kit. In a preferred embodiment, at least 2, for example 3, 4, 5,
6, 7, 8, 9, 10, vorzugsweise 15 bis 20 Markersequenzen oder 30 bis 50 oder 100 oder mehr Brustkrebs-spezifische 6, 7, 8, 9, 10, preferably 15 to 20 marker sequences or 30 to 50 or 100 or more breast cancer specific
Markersequenzen zusammen oder in Kombination verwendet, beispielsweise direkt nacheinander oder parallel. Der Nachweis einer Wechselwirkung der Körperflüssigkeit oder des Gewebeauszugs mit der oder den Brustkrebs-spezifischen Markersequenzen kann beispielsweise durch eine Sonde, Marker sequences used together or in combination, for example, directly in series or in parallel. The detection of an interaction of the body fluid or the tissue extract with the breast cancer-specific marker sequences or sequences, for example, by a probe,
insbesondere durch einen Antikörper erfolgen. especially by an antibody.
Eine besondere Ausführungsform der Erfindung betrifft das Verfahren, wobei das Stratifizieren oder die Therapiesteuerung Entscheidungen zur Behandlung und Therapie des Patienten, insbesondere Hospitalisierung des Patienten, Einsatz, Wirkung und / oder Dosierung eines oder mehrerer Arzneimittel, eine therapeutische Maßnahme oder die Überwachung eines A particular embodiment of the invention relates to the method, wherein stratification or therapy control Decisions for treatment and therapy of the patient, in particular hospitalization of the patient, use, effect and / or dosage of one or more drugs, a therapeutic measure or the monitoring of a patient
Krankheitsverlaufes sowie Therapieverlauf, Ätiologie oderDisease course and therapy course, etiology or
Klassifizierung einer Erkrankung samt Prognose umfasst. Ferner betrifft die Erfindung ein Verfahren zum Stratifizieren, insbesondere zur Risikostratifizierung und / oder Classification of a disease including prognosis includes. Furthermore, the invention relates to a method for stratifying, in particular for risk stratification and / or
Therapiesteuerung eines Patienten mit Brustkrebs. Ferner umfasst ist die Stratifizierung der Patienten mit Therapy control of a patient with breast cancer. Also included is the stratification of patients with
Brustkrebs in neue oder etablierte Subgruppen der Brustkrebs Patienten, sowie die sinnvolle Auswahl von Patientengruppen für die klinische Entwicklung von neuen Therapeutika. Der Begriff Therapiesteuerung umfasst ebenfalls die Einteilung von Patienten in Responder und Nicht-Responder bezüglich einer Therapie oder dessen Therapieverlauf.  Breast cancer in new or established subgroups of breast cancer patients, as well as the meaningful selection of patient groups for the clinical development of new therapeutics. The term therapy control also includes the classification of patients into responders and non-responders with regard to a therapy or its course of therapy.
„Diagnose" im Sinne dieser Erfindung bedeutet die positive Feststellung von Brustkrebs mittels der erfindungsgemäßen Brustkrebs-spezifischen Markersequenzen sowie die Zuordnung der Patienten zu Brustkrebs. Der Begriff der Diagnose umfasst die medizinische Diagnostik und diesbezügliche Untersuchungen, insbesondere die in-vitro Diagnostik und Labordiagnostik, ebenfalls Proteomics und Nukleinsäureblots . Weitere "Diagnosis" in the sense of this invention means the positive detection of breast cancer by means of the breast cancer-specific marker sequences according to the invention and the assignment of the patients to breast cancer.The term diagnosis includes medical diagnosis and investigations in this regard, in particular in vitro diagnostics and laboratory diagnostics Proteomics and nucleic acid blots
Untersuchungen können zur Absicherung und zum Ausschluss anderer Krankheiten vonnöten sein. Daher umfasst der Begriff Diagnose ebenfalls die Differentialdiagnose von Brustkrebs mittels der erfindungsgemäßen Brustkrebs-spezifischen Investigations may be needed to protect and exclude other diseases. Therefore, the term diagnosis also includes the differential diagnosis of breast cancer by means of the breast cancer-specific invention
MarkerSequenzen sowie die Prognose von Brustkrebs, Marker sequences as well as the prognosis of breast cancer,
insbesondere die Vorhersage des Risikos der Metastasenbildung. „Stratifizieren (auch: Stratifikation) oder Therapiesteuerung" im Sinne dieser Erfindung bedeutet, dass beispielsweise die erfindungsgemäßen Verfahren Entscheidungen zur Behandlung und Therapie des Patienten erlauben, sei es Hospitalisierung des Patienten, Einsatz, Wirkung und / oder Dosierung eines oder mehrerer Arzneimittel, eine therapeutische Maßnahme oder die Überwachung eines Krankheitsverlaufes sowie Therapieverlauf bzw. Ätiologie oder Klassifizierung einer Erkrankung, z.B. in einen neuen oder bestehenden Subtyp oder die Differenzierung von Krankheiten und dessen Patienten. in particular the prediction of the risk of metastasis. "Stratification (also: stratification) or therapy control" in the sense of this invention means that, for example, the methods according to the invention allow decisions for the treatment and therapy of the patient, be it hospitalization of the patient, use, effect and / or dosage of one or more drugs, a therapeutic one Measure or the monitoring of a course of disease as well as course of therapy or etiology or classification of a disease, eg in a new or existing subtype or the differentiation of diseases and their patients.
In einer weiteren Ausführungsform der Erfindung umfasst der Begriff „Stratifizierung" insbesondere die In a further embodiment of the invention, the term "stratification" includes in particular the
Risikostratifizierung mit der Prognose eines „outcome" eines nachteiligen gesundheitlichen Ereignisses. „Prognose" bedeutet die Vorhersage des Krankheitsverlaufs, beispielsweise die Vorhersage des Rezidiv-freien Überlebens, des Gesamtüberlebens, des Risikos der Metastasenbildung.  Risk stratification with the prognosis of an outcome of an adverse health event. "Prognosis" means the prediction of disease progression, for example the prediction of recurrence-free survival, overall survival, the risk of metastasis formation.
Im Rahmen dieser Erfindung wird unter „Patient" ein beliebiger Proband - Mensch oder Säugetier - verstanden, mit der Maßgabe, dass der Proband auf Brustkrebs untersucht wird. In the context of this invention, "patient" is understood to mean any test person - human or mammal - with the proviso that the subject is examined for breast cancer.
Der Begriff „Brustkrebs-spezifische Markersequenz (en) " im Sinne dieser Erfindung bedeutet, dass die Nukleinsäure, beispielsweise DNA, insbesondere cDNA oder RNA oder die kodierte Aminosäuresequenz oder das jeweils daraus erhältliche Polypeptid oder Protein signifikant (spezifisch) für The term "breast cancer-specific marker sequence (s)" in the sense of this invention means that the nucleic acid, for example DNA, in particular cDNA or RNA or the encoded amino acid sequence or the respective polypeptide or protein obtainable therefrom is significantly (specifically) for
Brustkrebs sind. Brustkrebs-spezifische Markersequenzen können Nukleinsäuresequenzen und Aminosäuresequenzen sein, wobei auch Modifikationen umfasst sind. „Brustkrebs-spezifisch" und „für Brustkrebs" bedeutet, dass beispielsweise die cDNA oder das jeweils daraus erhältliche Polypeptid oder Protein eine Wechselwirkung mit Substanzen aus der Körperflüssigkeit oder Gewebeauszug eines Patienten mit Brustkrebs aufweisen (z.B. Antigen (Epitop) / Antikörper Breast cancer are. Breast cancer-specific marker sequences may be nucleic acid sequences and amino acid sequences, including modifications. "Breast cancer-specific" and "for breast cancer" means that, for example, the cDNA or the respectively obtainable polypeptide or protein interact with substances from the body fluid or tissue extract of a patient with breast cancer (eg antigen (epitope) / antibody
(Paratop) Wechselwirkung) . Diese Substanzen aus der (Paratop) interaction). These substances from the
Körperflüssigkeit oder Gewebeauszug treten entweder nur oder zumindest verstärkt bei Brustkrebs auf beziehungsweise werden exprimiert, wohingegen diese Substanzen bei Patienten ohne Brustkrebs nicht oder zumindest in geringerem Maße (geringere Menge, geringere Konzentration) vorhanden sind. Brustkrebs¬ spezifische Markersequenzen können sich andererseits auch dadurch auszeichnen, dass sie eine Wechselwirkung mit Body fluid or tissue excision occur either only or at least increased in breast cancer or are expressed, whereas these substances are not present in patients without breast cancer, or at least to a lesser extent (smaller amount, lower concentration). ¬ breast cancer-specific marker sequences may also be characterized on the other hand that they interact with
Substanzen aus der Körperflüssigkeit oder Gewebeauszug von Patienten mit Brustkrebs eingehen, weil diese Substanzen nicht mehr oder zumindest in deutlich geringerer Menge/Konzentration bei Brustkrebs auftreten beziehungsweise exprimiert werden, wohingegen diese Substanzen bei Patienten ohne Brustkrebs vorhanden oder zumindest in deutlich höherem Maße vorhanden sind. Brustkrebs-spezifische Markersequenzen (Markersequenzen für Brustkrebs) können auch in gesunden Probanden vorhanden sein, jedoch verändert sich ihre Menge (Konzentration) beispielsweise bei der Entstehung, Etablierung und Therapie von Brustkrebs. Die Brustkrebs-spezifischen Markersequenzen sind deshalb Biomarker für Brustkrebs. Die Brustkrebs¬ spezifischen Markersequenzen können auf diese Weise ein Profil von Substanzen aus Körperflüssigkeit und Gewebeauszug Taking substances from the body fluid or tissue extract of patients with breast cancer, because these substances no longer occur or are expressed or expressed in significantly lower amount / concentration in breast cancer, whereas these substances are present in patients without breast cancer, or at least present in a much greater extent. Breast cancer-specific marker sequences (marker sequences for breast cancer) may also be present in healthy volunteers, but their amount (concentration) changes, for example, in the development, establishment and therapy of breast cancer. The breast cancer-specific marker sequences are therefore biomarkers for breast cancer. The breast cancer ¬ specific marker sequences can in this way a profile of substances from body fluid and tissue extract
abbilden, beispielsweise ein Brustkrebs-assoziiertes map, such as a breast cancer associated
Autoantikörperprofil . Autoantikörperprofile umfassen die Menge an einem oder Autoantibody profile. Autoantibody profiles include the amount of one or more
mehreren Autoantikörpern deren Vorkommen/Expression mit der Entstehung und/oder Etablierung von Brustkrebs einhergehen. „Brustkrebs-assoziierte Autoantikörperprofile" umfassen somit einerseits die Zusammensetzung (ein oder mehrere several autoantibodies whose occurrence / expression with the Origin and / or establishment of breast cancer go along. "Breast cancer-associated autoantibody profiles" thus include on the one hand the composition (one or more
Autoantikörper ) und anderseits die Menge/Konzentration Autoantibodies) and, on the other hand, the amount / concentration
einzelner Autoantikörper . single autoantibody.
In einer besonders bevorzugten Ausführungsform der Erfindung ist die Brustkrebs-spezifische Markersequenz ein Antigen oder ein Teil eines Antigens oder kodiert für ein Antigen oder für einen Teil eines Antigens. In einer besonders bevorzugten Ausführungsform erkennt /bindet die Brustkrebs-spezifische Markersequenz an Autoantikörper , die im Verlauf der Entstehung, Etablierung und Therapie von Brustkrebs (verstärkt) vorhanden sind oder in geringerem Maße (oder nicht mehr) vorhanden sind (nachfolgend „Brustkrebs- assoziierte Autoantikörper" ) . Autoantikörper werden vom Körper gegen körpereigene Antigene, die beispielsweise bei Brustkrebs entstehen, gebildet. Autoantikörper werden von Körper gegen unterschiedliche Substanzen und Pathogenen gebildet. Im Rahmen der vorliegenden Erfindung werden insbesondere die Brustkrebs- assoziierten Autoantikörper detektiert, die beim Auftreten und im Laufe der Entstehung von Brustkrebs gebildet werden In a particularly preferred embodiment of the invention, the breast cancer-specific marker sequence is an antigen or a part of an antigen or encodes an antigen or a part of an antigen. In a particularly preferred embodiment, the breast cancer-specific marker sequence recognizes / binds to autoantibodies present (enhanced), or to a lesser extent (or no longer), in the course of genesis, establishment and therapy of breast cancer (hereinafter "breast cancer-associated autoantibodies Autoantibodies are formed by the body against the body's own antigens, which are produced, for example, in breast cancer.Autoantibodies are formed by the body against different substances and pathogens. [Vorliegenden Im] In the context of the present invention, in particular the breast cancer-associated autoantibodies which are detected on the occurrence and in the course of time the formation of breast cancer are formed
und/oder in ihrer Expression hoch- beziehungsweise and / or in their expression high or
herunterreguliert werden. Brustkrebs-assozierte Autoantikörper können mit Hilfe der erfindungsgemäßen Verfahren und be down regulated. Breast cancer-associated autoantibodies can be detected using the methods of the invention and
Brustkrebs-spezifischer Markersequenzen nachgewiesen werden und somit als Indikation für Brustkrebs dienen. Der Nachweis und die Überwachung der Menge an Brustkrebs-assozierten Breast cancer-specific marker sequences are detected and thus serve as an indication for breast cancer. The detection and monitoring of the amount of breast cancer-associated
Autoantikörpern im Patienten kann zur Früherkennung, Diagnose und/oder Therapieüberwachung/Therapiesteuerung sowie zur Autoantibodies in the patient can be used for early detection, diagnosis and / or therapy monitoring / therapy control and for
Prognose und Vorhersage des Risikos der Metastasenbildung verwendet werden. Diese Brustkrebs-assoziierten Autoantikörperprofile können bereits bei Verwendung von einer Brustkrebs-spezifischen Markersequenz ausreichend Prognosis and prediction of the risk of metastasis formation can be used. These breast cancer-associated Autoantibody profiles may already be sufficient when using a breast cancer-specific marker sequence
charakterisiert werden. In anderen Fällen werden zwei oder mehr Brustkrebs-spezifische Markersequenzen notwendig sein, um ein Brustkrebs-assoziiertes Autoantikörperprofil abzubilden. be characterized. In other cases, two or more breast cancer-specific marker sequences will be necessary to map a breast cancer-associated autoantibody profile.
In bevorzugten Ausführungsformen der Erfindung können die Brustkrebs-assozierten Autoantikörper mit Brustkrebsspezifischen MarkerSequenzen nachgewiesen werden, die sich von einem anderen Individuum ableiten, weil sie beispielsweise aus einer kommerziellen cDNA-Bank stammen. Bevorzugte In preferred embodiments of the invention, the breast cancer-associated autoantibodies can be detected with breast cancer specific marker sequences derived from another individual, for example, from a commercial cDNA library. preferred
Ausführungsformen der Erfindung betreffen die Brustkrebs- assozierten Markersequenzen SEQ ID No . 1 - 491, SEQ ID. No . 492 - 982 und/oder Teilsequenzen von SEQ ID No . 1 - 982, und Sequenzen, die für die Proteine SEQ ID No . 983 bis 1473 und/oder Teilsequenzen dieser Proteine kodieren.  Embodiments of the invention relate to the breast cancer-associated marker sequences SEQ ID No. 1-491, SEQ ID. No. 492-982 and / or partial sequences of SEQ ID No. 1 - 982, and sequences coding for the proteins SEQ ID No. 983 to 1473 and / or partial sequences of these proteins.
In anderen bevorzugten Ausführungsformen der Erfindung können die Brustkrebs-assoziierten Autoantikörper mit Brustkrebsspezifischen MarkerSequenzen nachgewiesen werden, die sich von dem gleichen Individuum ableiten (Autoantigen) , weil sie beispielsweise aus einer eigens für den Patienten oder eine Gruppe von Patienten (beispielsweise im Rahmen der In other preferred embodiments of the invention, the breast cancer-associated autoantibodies can be detected with breast cancer specific marker sequences derived from the same individual (autoantigen), for example, from a patient specific or a group of patients (e.g.
individualisierten Medizin) hergestellten cDNA-Bank stammen. Beispielsweise werden dann Homologe der genannten Brustkrebs¬ spezifischen Markersequenzen SEQ ID. No . 1 - 1473 oder individualized medicine). For example, homologs of said breast cancer ¬ specific marker sequences SEQ ID. No. 1 - 1473 or
Teilsequenzen davon verwendet. Partial sequences used by it.
Autoantikörper können bereits viele Jahre vor Auftreten der ersten Krankheitssymptome vom Patienten gebildet werden. Damit wäre eine Früherkennung, Diagnose und auch Prognose und Autoantibodies can be formed by the patient many years before the onset of the first disease symptoms. This would be an early detection, diagnosis and also prognosis and
(vorbeugende) Behandlung bereits Jahre vor dem sichtbaren Krankheitsausbruch möglich. Die erfindungsgemäßen Vorrichtungen und Mittel (Anordnung, Array, Proteinarray, Diagnostikum, Test Kit) und Verfahren ermöglichen somit ein im Vergleich zu bekannten Verfahren sehr frühes Eingreifen, was die Prognose und Überlebensraten deutlich verbessert. Da sich die Brustkrebs-assoziierten Autoantikörperprofile während der Etablierung und Behandlung/Therapie von Brustkrebs (preventive) treatment already possible years before the visible onset of disease. The invention Devices and means (array, array, protein array, diagnostic, test kit) and methods thus allow very early intervention compared to known methods, which significantly improves prognosis and survival rates. As the breast cancer-associated autoantibody profiles during the establishment and treatment / treatment of breast cancer
verändern, ermöglicht die Erfindung auch den Nachweis und die Überwachung von Brustkrebs in jedem Stadium der Entstehung und Behandlung sowie die Überwachung im Rahmen der The invention also makes it possible to detect and monitor breast cancer at any stage of its development and treatment, as well as under surveillance
Brustkrebsnachsorge. Die erfindungsgemäßen Mittel erlauben auch eine einfache Handhabung zu Hause durch den Patienten und die kostengünstige routinemäßige Vorsorge zur Früherkennung. Breast cancer follow-up care. The agents of the invention also allow for easy home handling by the patient and cost-effective routine screening for early detection.
Insbesondere durch die Verwendung von Antigenen als In particular, by the use of antigens as
spezifische Markersequenz für Brustkrebs, die sich von bereits bekannten Sequenzen, z.B. aus kommerziellen cDNA Banken, ableiten, können Probanden getestet und gegebenenfalls specific marker sequence for breast cancer derived from previously known sequences, e.g. derived from commercial cDNA banks, subjects can be tested and optionally
vorhandene Brustkrebs-assoziierte Autoantikörper in diesen Probanden nachgewiesen werden, auch wenn bei diesen Probanden die entsprechenden Autoantigene (noch) nicht bekannt sind. Verschiedene Patienten können unterschiedliche Brustkrebs¬ assoziierte Autoantikörperprofile aufweisen, beispielsweise unterscheiden sich verschiedene Kohorten oder Existing breast cancer-associated autoantibodies are detected in these subjects, even if the corresponding autoantigens are (still) not known in these subjects. Different patients may have different breast cancer ¬ associated autoantibody profiles, for example, to distinguish between different cohorts or
Bevölkerungsgruppen. Jeder Patient kann dabei ein oder mehrere verschiedene Brustkrebs-assoziierte Autoantikörper im Laufe der Entstehung von Brustkrebs und des Fortschreitens der  Populations. Each patient may have one or more different autoantibodies associated with breast cancer in the course of breast cancer and the progression of breast cancer
Brustkrebserkrankung, d.h. ebenfalls verschiedene Breast cancer disease, i. also different
Autoantikörperprofile, bilden. Außerdem kann sich die Autoantibody profiles, form. In addition, the
Zusammensetzung und/oder die Menge der gebildeten Brustkrebsspezifischen Autoantikörper im Laufe der Brustkrebs Entstehung und des Fortschreitens der Krankheit verändern, so dass eine quantitative Auswertung notwendig wird. Auch die Therapie/Behandlung von Brustkrebs führt zu Veränderungen in der Zusammensetzung und/oder der Menge an Brustkrebsassoziierten Autoantikörpern . Die große Auswahl an Composition and / or the amount of breast cancer-specific autoantibodies formed in the course of breast cancer development and progression of the disease change, so that a quantitative evaluation is necessary. Also the Therapy / treatment of breast cancer leads to changes in the composition and / or amount of breast cancer-associated autoantibodies. The large selection of
erfindungsgemäßen Brustkrebs-spezifischen Markersequenzen ermöglichen die individuelle Zusammenstellung von Brustkrebsspezifischen MarkerSequenzen in einer Anordnung für einzelne Patienten, Gruppen von Patienten, bestimmte Kohorten, breast cancer-specific marker sequences according to the invention enable the individual compilation of breast cancer-specific marker sequences in an arrangement for individual patients, groups of patients, specific cohorts,
Bevölkerungsgruppen und dergleichen. Im Einzelfall kann deshalb die Verwendung einer Brustkrebs-spezifischen Population groups and the like. In individual cases, therefore, the use of a breast cancer-specific
Markersequenz ausreichen, während in anderen Fällen mindestens zwei oder mehr Brustkrebs-spezifische Markersequenzen zusammen oder in Kombination verwendet werden müssen um ein Marker sequence sufficient, while in other cases, at least two or more breast cancer-specific marker sequences must be used together or in combination
aussagekräftiges Autoantikörperprofil zu erstellen. to create a meaningful autoantibody profile.
Der Nachweis von Brustkrebs-assoziierten Autoantikörpern beispielsweise im Serum/Plasma hat gegenüber anderen The detection of breast cancer-associated autoantibodies, for example, in serum / plasma has over others
Biomarkern den Vorteil einer hohen Stabilität und Biomarkers have the advantage of high stability and
Lagerfähigkeit und einer guten Nachweisbarkeit. Auch Shelf life and good traceability. Also
unterliegt die Anwesenheit von Autoantikörpern keinem the presence of autoantibodies is not subject to any
circardianen Rhythmus, so dass die Probennahme unabhängig von Tageszeit, Nahrungsaufnahme und dergleichen ist. circadian rhythm, so that the sampling is independent of time of day, food intake and the like.
Daneben können die Brustkrebs-assoziierten Autoantikörper mit Hilfe der korrespondierenden Antigene/Autoantigene in In addition, the breast cancer-associated autoantibodies can be detected using the corresponding antigens / autoantigens in
bekannten Assays wie z.B. ELISA oder Western-Blot nachgewiesen werden und auf dieses die Ergebnisse überprüft werden. Im Sinne der Erfindung bedeutet „wobei eine oder mehrere known assays such as e.g. ELISA or Western Blot can be detected and the results are checked. For the purposes of the invention, "one or more
Brustkrebs-spezifische Markersequenz (en) ausgewählt Breast cancer specific marker sequence (s) selected
wird/werden" und „wobei eine oder mehrere Markersequenz (en) für Brustkrebs ausgewählt wird/werden", dass eine will be "and" wherein one or more marker sequence (s) are selected for breast cancer "that a
Wechselwirkung nachgewiesen wird. Eine solche Wechselwirkung ist z.B. eine Bindung, insbesondere eine bindende Substanz an mindestens eine Brustkrebs-spezifische Markersequenz oder im Fall, dass die Brustkrebs-spezifische Markersequenz eine Interaction is detected. Such an interaction is for example a bond, in particular a binding substance at least one breast cancer specific marker sequence or in case the breast cancer specific marker sequence has one
Nukleinsäure, beispielsweise eine cDNA ist, die Hybridisierung mit einer geeigneten Substanz unter gewählten Bedingungen, insbesondere stringenten Bedingungen (z.B. wie üblich Nucleic acid, for example a cDNA, is the hybridization with a suitable substance under chosen conditions, in particular stringent conditions (for example as usual
definiert in J. Sambrook, E.F. Fritsch, T. Maniatis (1989), Molecular cloning: A laboratory manual, 2nd Edition, Cold Spring Habor Laboratory Press, Cold Spring Habor, USA oder Ausubel, "Current Protocols in Molecular Biology", Green defined in J. Sambrook, E.F. Fritsch, T. Maniatis (1989), Molecular cloning: A laboratory manual, 2nd Edition, Cold Spring Habor Laboratory Press, Cold Spring Habor, USA, or Ausubel, "Current Protocols in Molecular Biology," Green
Publishing Associates and Wiley Interscience, N.Y. (1989)). Ein Beispiel für stringente Hybridisierungsbedingungen ist: Hybridisierung in 4 x SSC bei 65° C (alternativ in 50% Publishing Associates and Wiley Interscience, N.Y. (1989)). An example of stringent hybridization conditions is: hybridization in 4 × SSC at 65 ° C. (alternatively in 50%
Formamid und 4 X SSC bei 42° C) , gefolgt von mehreren Formamide and 4X SSC at 42 ° C), followed by several
Waschschritten in 0,1 x SSC bei 65°C für insgesamt etwa eine Stunde. Ein Beispiel für wenig stringente Washes in 0.1 x SSC at 65 ° C for a total of about one hour. An example of less stringent
Hybridisierungsbedingungen ist Hybridisierung in 4 x SSC bei 37° C, gefolgt von mehreren Waschritten in 1 x SSC bei  Hybridization conditions is hybridization in 4 x SSC at 37 ° C followed by several washing steps in 1 x SSC
Raumtemperatur . Room temperature.
Die Wechselwirkung zwischen der Körperflüssigkeit oder The interaction between the body fluid or
Gewebeauszuges eines Patienten und den Brustkrebs-spezifischen MarkerSequenzen ist vorzugsweise eine Protein-Protein Tissue extraction of a patient and the breast cancer specific marker sequences is preferably a protein-protein
Wechselwirkung . Interaction.
Solche Substanzen, beispielsweise Antigene, Autoantigene, Brustkrebs-assoziierte Autoantikörper , sind erfindungsgemäß Bestandteil einer Körperflüssigkeit, insbesondere Blut, Such substances, for example antigens, autoantigens, breast cancer-associated autoantibodies, are part of a body fluid, in particular blood, according to the invention.
Vollblut, Blutplasma, Blutserum, Patientenserum, Urin, Whole blood, blood plasma, blood serum, patient serum, urine,
Cerebrospinalflüssigkeit , Synovialflüssigkeit oder eines Gewebeauszuges, beispielsweise aus Tumorgewebe des Patienten. Die Erfindung betrifft insbesondere die Verwendung dieser Körperflüssigkeiten und Gewebeauszüge für Früherkennung, Diagnose, Prognose, Therapiesteuerung und Nachsorge. In einer weiteren Ausführungsform der Erfindung können jedoch die Brustkrebs-spezifischen Markersequenzen bzw. die von diesen Markersequenzen erkannten Substanzen, beispielsweise Brustkrebs-assoziierte Autoantikörper , in einer signifikant höheren oder niedrigeren Expressionsrate oder Konzentration vorliegen, was auf Brustkrebs hinweist. Hierbei werden mittels Proteomics oder Nukleinsäureblots die relativen Cerebrospinal fluid, synovial fluid or a tissue extract, for example from tumor tissue of the patient. In particular, the invention relates to the use of these body fluids and tissue extracts for early detection, diagnosis, prognosis, therapy control and aftercare. In a further embodiment of the invention, however, the breast cancer-specific marker sequences or the substances recognized by these marker sequences, for example breast cancer-associated autoantibodies, may be present at a significantly higher or lower expression rate or concentration, which indicates breast cancer. Here are the proteomics or nucleic acid blots the relative
Expressionsraten krank / gesund der erfindungsgemäßen Expression rates ill / healthy of the invention
MarkerSequenzen für Brustkrebs bzw. die von diesen Marker sequences for breast cancer or those of these
Markersequenzen erkannten Substanzen bestimmt. Marker sequences detected substances determined.
Die Brustkrebs-spezifischen Markersequenzen verfügen in einer weiteren Ausführungsform der Erfindung über ein The breast cancer-specific marker sequences in a further embodiment of the invention have a
Erkennungssignal, welches an die zu bindende Substanz Detection signal, which to the substance to be bound
adressiert ist (z.B. Antikörper, Nukleinsäure). addressed (e.g., antibody, nucleic acid).
Erfindungsgemäß bevorzugt ist für ein Protein das According to the invention, the protein is preferred for a protein
Erkennungssignal ein Epitop und / oder Paratop und / oder Hapten und für eine cDNA eine Hybridisierungs- oder  Detection signal an epitope and / or paratope and / or hapten and cDNA for a hybridization or
Bindungsregion . Binding region.
Die erfindungsgemäßen Brustkrebs-spezifischen Markersequenzen sind Gegenstand der Tabelle A (RNA) und können durch den jeweilig zitierten Datenbankeintrag (auch mittels Internet: http://www.ncbi.nlm.nih.gov/) eindeutig identifiziert werden (mittels Accession No . ) , siehe ebenfalls das zugehörige The breast cancer-specific marker sequences according to the invention are the subject of Table A (RNA) and can be clearly identified by the respectively cited database entry (also by means of the Internet: http://www.ncbi.nlm.nih.gov/) (by means of accession no.). , see also the corresponding
Sequenzprotokoll. Die Klonsequenzen (cDNA) und Sequence Listing. The clone sequences (cDNA) and
Proteinsequenzen sind im anliegenden Sequenzprotokoll zu finden . Protein sequences can be found in the attached sequence listing.
Daher umfasst die Erfindung ebenfalls die Volllängesequenzen der erfindungsgemäßen Brustkrebs-spezifischen Markersequenzen und zwar wie über den bekannten Datenbankeintrag gemäß Tabelle A definiert, nachstehend SEQ ID No . 1 - 1473 genannt. Weiterhin umfasst sind daher ebenfalls analoge Therefore, the invention also encompasses the full-length sequences of the breast cancer-specific marker sequences according to the invention, namely as defined by the known database entry according to Table A, SEQ ID NO. 1 - 1473 called. Furthermore, therefore, also include analog
Ausführungsformen zu den Brustkrebs-spezifischen Embodiments to the breast cancer-specific
Markersequenzen SEQ ID NO. 1 - 1473, wie z.B. in den Marker sequences SEQ ID NO. 1 - 1473, such as in the
Ansprüchen dargelegt, da die erfindungsgemäßen SEQ 1 -1473 wiederum Teilsequenzen, zumindest mit hoher Homologie, darstellen. Die Brustkrebs-spezifischen Markersequenzen SEQ 1- 1473 sind jedoch erfindungsgemäß bevorzugt. Claims set forth, since the SEQ 1 -1473 invention again represent partial sequences, at least with high homology. However, the breast cancer-specific marker sequences SEQ 1-1473 are preferred according to the invention.
Erfindungsgemäß umfassen die Markersequenzen auch solche According to the invention, the marker sequences also include such
Modifikationen der Nukleinsäuresequenz, insbesondere cDNA- Sequenz und der entsprechenden Aminosäuresequenz, wie Modifications of the nucleic acid sequence, in particular cDNA sequence and the corresponding amino acid sequence, such as
chemische Modifikation, wie Citrullinierung, Acetylierung, Phosphorylierung, Glykosilierung oder polyA-Strang und chemical modification, such as citrullination, acetylation, phosphorylation, glycosylation or polyA strand and
weiteren dem Fachmann einschlägig bekannte Modifikationen. further modifications known to the person skilled in the art.
Die Erfindung betrifft auch Homologe der Brustkrebs- spezifischen Markersequenzen und Teilsequenzen, beispielsweise Fragmente von Brustkrebs-spezifischen Markersequenzen. The invention also relates to homologs of breast cancer-specific marker sequences and partial sequences, for example fragments of breast cancer-specific marker sequences.
Homologe sind beispielsweise Nukleinsäure- und/oder Homologs are, for example, nucleic acid and / or nucleic acid
Proteinsequenzen, beispielsweise Homologe von SEQ ID No. 1 - 1473, insbesondere Homologe von SEQ ID No . 1-491 und SEQ ID No . 492- 982 die eine Identität mit den Brustkrebs¬ spezifischen Markersequenzen von mindestens 70 % oder 80 %, vorzugsweise 90 % oder 95 %, besonders bevorzugt 96 % oder 97 % oder mehr, beispielsweise 98 % oder 99 % aufweisen. In einer besonders bevorzugten Ausführungsform der Erfindung beträgt für den Fall, dass es sich bei den Brustkrebs-spezifischen Markersequenzen um Antigene handelt, die Homologie im Protein sequences, for example homologs of SEQ ID no. 1 - 1473, in particular homologs of SEQ ID No. 1-491 and SEQ ID No. 492-982 having an identity with the breast cancer ¬ specific marker sequences of at least 70% or 80%, preferably 90% or 95%, more preferably 96% or 97% or more, for example 98% or 99%. In a particularly preferred embodiment of the invention, in the event that the breast cancer-specific marker sequences are antigens, the homology in
Sequenzbereich in dem die Antigen-Antikörper- beziehungsweise Antigen-Autoantikörper-Wechselwirkung stattfindet mindestens 95 %, vorzugsweise mindestens 97 %, besonders bevorzugt mindestens 99 %. Erfindungsgemäß umfasst sind beispielsweise Mutationen wie Basenaustauschmutationen, Rastermutationen, Baseneinschubmutationen, Basenverlustmutationen, Sequence area in which the antigen-antibody or antigen-autoantibody interaction takes place at least 95%, preferably at least 97%, particularly preferably at least 99%. For example, according to the invention Mutations such as base-exchange mutations, raster mutations, base insertion mutations, base-loss mutations,
Punktmutationen, Insertionsmutationen . Point mutations, insertion mutations.
Gegenstand der Erfindung sind auch Teilsequenzen der The invention also subsequences of
Brustkrebs-spezifischen Markersequenzen. Teilsequenzen Breast cancer-specific marker sequences. partial sequences
umfassen auch Fragmente der erfindungsgemäßen Markersequenzen, Teilsequenzen sind solche Nukleinsäuren oder Proteine/Peptide, die gegenüber der vollständigen Nukleinsäure oder dem also include fragments of the marker sequences according to the invention, partial sequences are those nucleic acids or proteins / peptides which are opposite to the complete nucleic acid or the
vollständigen Protein/Peptid verkürzt sind. Die Deletion kann sich dabei an dem oder den Ende und/oder innerhalb der Sequenz befinden. Umfasst sind beispielsweise Teilsequenzen und/oder Fragmente die 50 bis 100 Nukleotide, 70-120 Nukleotide einer vollständigen Sequenz aufweisen, beispielsweise von SEQ 1- 1473. Homologe von Teilsequenzen und Fragmenten sind ebenfalls erfindungsgemäß umfasst. In einer besonderen Ausführungsform sind die Brustkrebs-spezifischen Markersequenzen gegenüber den Sequenzen 1 - 1473 so weit verkürzt, dass sie nur noch aus der/den Bindungsstellen für den betreffenden Brustkrebsassoziierten Autoantikörper bestehen. Erfindungsgemäß umfasst sind auch Brustkrebs-spezifische Markersequenzen, die sich von den Sequenzen SEQ ID No. 1 - 1473 dadurch unterscheiden, dass sie ein oder mehrere Insertionen beinhalten, wobei die shortened complete protein / peptide. The deletion may be at or near the end and / or within the sequence. For example, partial sequences and / or fragments comprising 50 to 100 nucleotides, 70-120 nucleotides of a complete sequence, for example of SEQ ID 1473, are included. Homologs of partial sequences and fragments are also included according to the invention. In a particular embodiment, the breast cancer-specific marker sequences compared to the sequences 1-1473 are shortened so that they consist only of the / the binding sites for the relevant breast cancer associated autoantibodies. Breast cancer-specific marker sequences which differ from the sequences SEQ ID no. 1 - 1473 in that they contain one or more insertions, the
Insertionen beispielsweise 1 bis 100 oder mehr Insertions, for example, 1 to 100 or more
Nukleotide/Aminosäuren, vorzugsweise 5 bis 50, besonders bevorzugt 10 bis 20 Nukleotide/Aminosäuren lang sind und die Sequenzen aber ansonsten identisch oder homolog zu den Nucleotides / amino acids, preferably 5 to 50, more preferably 10 to 20 nucleotides / amino acids in length and the sequences otherwise identical or homologous to the
Sequenzen 1 - 1473 sind. Besonders bevorzugt sind Sequences 1 - 1473 are. Particularly preferred
Teilsequenzen, die mindestens 90%, vorzugsweise mindestens 95 %, besonders bevorzugt mindestens 97 % oder 98 % der Länge der erfindungsgemäßen Brustkrebs-spezifischen Markersequenzen, SEQ ID No. 1 -491, SEQ ID. No . 492 - 982, SEQ ID No . 983 - 1473 aufweisen. Erfindungsgemäß umfasst sind ebenfalls Homologe der TeilSequenzen . Partial sequences which are at least 90%, preferably at least 95%, particularly preferably at least 97% or 98%, of the length of the breast cancer-specific marker sequences according to the invention, SEQ ID no. 1 -491, SEQ ID. No. 492-982, SEQ ID No. 983 - 1473 exhibit. Also included according to the invention are homologs of the partial sequences.
In einer weiteren Ausführungsform kann die jeweilige In a further embodiment, the respective
Brustkrebs-spezifische Markersequenz in unterschiedlichen Mengen in einem oder mehreren Bereichen in der Anordung oder auf dem Träger repräsentiert sein. Dies erlaubt eine Variation der Sensitivität . Die Bereiche können jeweils eine Gesamtheit von Brustkrebs-spezifischen Markersequenzen aufweisen, d.h. eine genügende Zahl an verschiedenen Brustkrebs-spezifischen Markersequenzen, insbesondere 2, 3, 4, 5, 6, 7, 8, 9 oder 10 oder mehr verschiedene und gegebenenfalls weitere Breast cancer-specific marker sequence may be represented in varying amounts in one or more regions in the array or on the carrier. This allows a variation of the sensitivity. The regions may each comprise a total of breast cancer-specific marker sequences, i. a sufficient number of different breast cancer-specific marker sequences, in particular 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more different and optionally further
Nukleinsäuren und/oder Proteinen, insbesondere Biomarker. Nucleic acids and / or proteins, in particular biomarkers.
In einer besonders bevorzugten Ausführungsform der Erfindung sind mindestens 96 bis 25.000 (numerisch) oder mehr In a particularly preferred embodiment of the invention, at least 96 to 25,000 (numerically) or more
verschiedene oder gleiche Brustkrebs-spezifische different or same breast cancer-specific
Markersequenzen und gegebenenfalls weitere Nukleinsäuren und/oder Proteinen, insbesondere Biomarker auf dem Träger repräsentiert. Weiterhin bevorzugt sind mehr als 2.500, besonders bevorzugt 10.000 oder mehr verschiedene oder gleiche Brustkrebs-spezifische Markersequenzen und gegebenenfalls weitere Nukleinsäuren und/oder Proteine, insbesondere  Marker sequences and optionally further nucleic acids and / or proteins, in particular biomarkers represented on the carrier. Also preferred are more than 2,500, more preferably 10,000 or more different or identical breast cancer-specific marker sequences and optionally further nucleic acids and / or proteins, in particular
Biomarker auf dem Träger repräsentiert. Biomarker on the carrier represents.
Im Rahmen dieser Erfindung bedeutet „Anordnung" synonym „Array" und sofern dieser „Array" zur Identifizierung von Substanzen an Brustkrebs-spezifischen Markersequenzen In the context of this invention, "arrangement" synonymously means "array" and provided that "array" for the identification of substances on breast cancer-specific marker sequences
verwendet wird, ist hierunter vorzugsweise ein „Assay" oder eine diagnostische Vorrichtung zu verstehen. In einer is used, this is preferably an "assay" or a diagnostic device to understand
bevorzugten Ausführungsform ist die Anordnung derart preferred embodiment, the arrangement is such
gestaltet, dass die auf der Anordnung repräsentierten Brust- krebs-spezifischen Markersequenzen in Form eines Gitters auf einem Träger vorliegen. Ferner sind solche Anordnungen designed that the breast cancer-specific marker sequences represented on the array in the form of a grid on present to a carrier. Further, such arrangements
bevorzugt, die eine hochdichte (high-density ) Anordnung von Brustkrebs-spezifischen Markersequenzen, beispielsweise preferred, which is a high-density (high-density) array of breast cancer-specific marker sequences, for example
Proteinbindern erlauben. Vorzugsweise werden die Brustkrebs- spezifischen Markersequenzen gespottet. Solche hochdichte gespotteten Anordnungen sind beispielsweise in der WO 99/57311 und WO 99/57312 offenbart und können vorteilhaft in einem robotergestützten automatisierten High-Throughput Verfahren zur Anwendung kommen. Im Rahmen dieser Erfindung umfasst jedoch der Begriff „Assay" oder diagnostische Vorrichtung ebenfalls solche Allow protein binders. Preferably, the breast cancer-specific marker sequences are spotted. Such high density spotted assemblies are disclosed, for example, in WO 99/57311 and WO 99/57312, and may be advantageously used in a robotic automated high throughput method. In the context of this invention, however, the term "assay" or diagnostic device also includes such
Ausführungsformen einer Vorrichtung, wie ELISA, Bead-based Assay, Line Assay, Western Blot, immunchromatographische Embodiments of a device such as ELISA, bead-based assay, line assay, Western blot, immunochromatographic
Verfahren (z.B. so genannte Lateral Flow Immunoassays ) oder ähnliche immunologische Single- oder Multiplex- Nachweisverfahren . Methods (e.g., so-called lateral flow immunoassays) or similar immunological single or multiplex detection methods.
Ein „Proteinarray" im Sinne dieser Erfindung ist die A "protein array" in the sense of this invention is the
systematische Anordnung von Brustkrebs-spezifischen systematic arrangement of breast cancer-specific
Markersequenzen auf einem festen Träger, wobei die Brustkrebs- spezifischen Markersequenzen Proteine oder Peptide oder Teile davon sind und wobei der Träger jede beliebige Form und/oder Größe haben kann und wobei der Träger vorzugsweise ein fester Träger ist. Solid support carrier sequences, wherein the breast cancer specific marker sequences are proteins or peptides or portions thereof and wherein the carrier may be of any shape and / or size and wherein the carrier is preferably a solid carrier.
Die Brustkrebs-spezifischen Markersequenzen der Anordnung sind auf einen Träger fixiert, vorzugsweise jedoch gespottet oder immobilisiert gar aufgedruckt, d.h. reproduzierbar The breast cancer specific marker sequences of the assembly are fixed to a support, but preferably spotted or immobilized even printed, i. reproducible
aufgebracht. Ein oder mehrere Brustkrebs-spezifische applied. One or more breast cancer-specific
Markersequenzen können mehrfach in der Gesamtheit aller Marker sequences can be duplicated in the totality of all
Brustkrebs-spezifischen Markersequenzen präsent sein und in unterschiedlichen Mengen bezogen auf einen Spot vorliegen. Ferner können die Brustkrebs-spezifischen Markersequenzen auf dem Träger standardisiert sein (z.B. mittels serieller Breast cancer-specific marker sequences be present and available in different amounts based on a spot. Furthermore, the breast cancer-specific marker sequences may be standardized on the carrier (eg by serial
Verdünnungsreihen von z.B. Humanglobulinen als interne Serial dilutions of e.g. Human globulins as internal
Kaiibratoren zur Datennormalisierung und quantitativen Calibrators for data normalization and quantitative
Auswertung) . Gegenenfalls kann auch ein Standard (z.B. ein Gold Standard) auf dem Träger aufgebracht sein. Evaluation). If desired, a standard (e.g., a gold standard) may also be applied to the carrier.
In einer weiteren Ausführungsform liegen die Brustkrebsspezifischen Markersequenzen als Klone vor. Solche Klone können beispielsweise mittels einer erfindungsgemäßen cDNA- Expressionsbibliothek erhalten werden (Büssow et al . 1998In a further embodiment, the breast cancer specific marker sequences are present as clones. Such clones can be obtained, for example, by means of a cDNA expression library according to the invention (Büssow et al., 1998
(Supra)) . In einer bevorzugten Ausführungsform werden solche Expressionsbibliotheken enthaltend Klone mittels (Supra)). In a preferred embodiment, such expression libraries containing clones by means
Expressionsvektoren aus einer exprimierenden cDNA Bibliothek bestehend aus den cDNA Markersequenzen erhalten. Diese Expression vectors obtained from an expressing cDNA library consisting of the cDNA marker sequences. These
Expressionsvektoren enthalten vorzugsweise induzierbare Expression vectors preferably contain inducible
Promotoren. Die Induktion der Expression kann z.B. mittels eines Induktors, solche wie IPTG, erfolgen. Geeignete  Promoters. Induction of expression may be e.g. by means of an inductor, such as IPTG. suitable
Expressionsvektoren sind beschrieben in Terpe et al . (Terpe T Appl Microbiol Biotechnol. 2003 Jan; 60 ( 5 ) : 523-33 ) . Expressionsbibliotheken sind dem Fachmann bekannt, diese können nach Standardwerken, wie Sambrook et al, "Molecular Cloning, A laboratory handbook, 2nd edition (1989), CSH press, Cold Spring Harbor, New York hergestellt werden. Weiterhin bevorzugt sind solche Expressionsbibliotheken, die Expression vectors are described in Terpe et al. (Terpe T Appl Microbiol Biotechnol 2003 Jan; 60 (5): 523-33). Expression libraries are known to the person skilled in the art, these can be prepared according to standard works, such as Sambrook et al., Molecular Cloning, Laboratory Laboratory, 2nd edition (1989), CSH press, Cold Spring Harbor, New York Further preferred are such expression libraries
gewebespezifisch sind (z.B. humanes Gewebe, insbesondere humane Organe, beispielsweise aus Brustgewebe oder Gewebe aus Mammakarzinom) . Ferner sind erfindungsgemäß ebenfalls solche Expressionsbibliotheken mit eingeschlossen, die mittels exon- trapping erhalten werden können. Statt Expressionsbibliothek kann synonym von einer Expressionsbank gesprochen werden. Weiterhin bevorzugt sind Proteinarrays oder entsprechende Expressionsbibliotheken, die keine Redundanz aufweisen (so genannte: Uniclone®-Bibliothek ) und nach den Lehren der WO 99/57311 und WO 99/57312 beispielsweise hergestellt werden können. Diese bevorzugten Uniclone- Bibliotheken weisen einen hohen Anteil an nicht-fehlerhaften vollständig exprimierten Proteinen einer cDNA-Expressionsbibliothek auf. are tissue-specific (eg human tissue, in particular human organs, for example from breast tissue or tissue from breast cancer). Furthermore, such expression libraries are also included according to the invention, which can be obtained by exon trapping. Instead of expression library can be spoken synonymously from an expression bank. Further preferred are protein arrays or corresponding expression libraries which have no redundancy (so-called: Uniclone® library) and can be prepared, for example, according to the teachings of WO 99/57311 and WO 99/57312. These preferred Uniclone libraries have a high content of non-defective, fully expressed proteins of a cDNA expression library.
Im Rahmen dieser Erfindung können die Klone ebenfalls nicht abschließend solche sein wie transformierte Bakterien, rekombinante Phagen oder transformierte Zellen von Säugern, Insekten, Pilzen, Hefen oder Pflanzen. In the context of this invention as well, the clones may not be such as transformed bacteria, recombinant phage or transformed cells of mammals, insects, fungi, yeasts or plants.
Die Klone werden auf einen festen Träger fixiert, gespottet oder immobilisiert. Daher betrifft die Erfindung eine The clones are fixed on a solid support, spotted or immobilized. Therefore, the invention relates to a
Anordnung/Verwendung, wobei die Brustkrebs-spezifischen Arrangement / use, being the breast cancer-specific
Markersequenzen als Klone vorliegen. Marker sequences are present as clones.
Zusätzlich können die Brustkrebs-spezifischen Markersequenzen in der jeweiligen Form in Form eines Fusionsproteins In addition, the breast cancer-specific marker sequences may be in the form of a fusion protein
vorliegen, welches beispielsweise mindestens ein present, which for example at least one
Affinitätsepitop oder "Tag" enthält. Der Tag kann ein solcher sein wie c-myc, His-Tag, Arg-tag, FLAG, alkalische Contains affinity epitope or "tag". The day can be one such as c-myc, His-tag, Arg-tag, FLAG, alkaline
Phosphatase, V5-Tag, T7-Tag oder Strep-Tag, HAT-tag, NusA, S- tag, SBP-tag, Thioredoxin, DsbA, ein Fusionsprotein,  Phosphatase, V5 tag, T7 tag or strep tag, HAT tag, NusA, S tag, SBP tag, thioredoxin, DsbA, a fusion protein,
vorzugsweise eine Cellulose-bindende Domäne, preferably a cellulose-binding domain,
grünfluoreszierendes Protein, Maltose bindendes Protein, Calmodulin-bindendes Protein, Glutathione S-transferase oder lacZ enthalten. green fluorescent protein, maltose binding protein, calmodulin binding protein, glutathione S-transferase or lacZ.
In einer weiteren bevorzugten Ausführungsform der In a further preferred embodiment of the
erfindungsgemäßen Anordnung/Verwendung entspricht diese einem Gitter, dass die Größenordnung einer Mikrotiterplatte (8-12 Wells Streifen, 96 Wells, 384 Wells oder mehr) , eines Silizium-Wafers, eines Chips, eines massenspektrometrischen Targets oder einer Matrix besitzt. According to the arrangement / use of this invention corresponds to a grid that the order of a microtiter plate (8-12 wells strips, 96 wells, 384 wells or more), one Has silicon wafers, a chip, a mass spectrometric target or a matrix.
In einer weiteren Ausführungsform betrifft die Erfindung einen Assay oder Proteinarray zum Identifizieren und In a further embodiment, the invention relates to an assay or protein array for identification and
Charakterisieren einer Substanz (beispielsweise auch Hit, LeitSubstanz , Kandidat, Wirkstoff) für Brustkrebs, dadurch gekennzeichnet, dass eine erfindungsgemäße Anordnung oder Assay mit a. ) mindestens einer zu untersuchenden Substanz in Kontakt gebracht wird und b. ) ein Bindungserfolg nachgewiesen wird. Characterizing a substance (for example, hit, conductive substance, candidate, active ingredient) for breast cancer, characterized in that an arrangement or assay according to the invention with a. ) is brought into contact with at least one substance to be examined and b. ) a binding success is detected.
Die zu untersuchende Substanz kann ein beliebiges natives oder nicht-natives Biomolekül, ein (synthetisches) chemisches Molekül, ein Naturstoff, eine Mischung oder eine The substance to be investigated may be any native or non-native biomolecule, a (synthetic) chemical molecule, a natural product, a mixture or a
Substanzbibliothek sein. Substance library.
Nachdem die zu untersuchende Substanz eine Brustkrebs¬ spezifische Markersequenz kontaktiert hat, erfolgt die After the substance to be examined has contacted a breast cancer ¬ specific marker sequence, the
Auswertung des Bindungserfolges, beispielsweise unter Evaluation of the binding success, for example under
Verwendung mit handelsüblicher Image-Analyse Software (GenePix Pro (Axon Laboratories), Aida (Raytest), ScanArray (Packard Bioscience) . Use with commercially available image analysis software (GenePix Pro (Axon Laboratories), Aida (Raytest), ScanArray (Packard Bioscience).
Die Visualisierung erfindungsgemäßer Bindungen, The visualization of bonds according to the invention,
Bindungserfolge, Wechselwirkungen wie Protein-Protein- Wechselwirkungen (z.B. Protein an Brustkrebs-spezifische Binding results, interactions such as protein-protein interactions (e.g., breast cancer specific protein
Markersequenz, wie Antigen/Antikörper ) oder entsprechendeMarker sequence, such as antigen / antibody) or equivalent
„Mittel zum Nachweis des Bindungserfolges" kann beispielsweise mittels Fluoresenzmarkierung, Biotiniylierung, Radio-Isotopen- Markierung oder kolloidale Gold- oder Latex-Partikel- Markierung in üblicher Weise erfolgen. Ein Nachweis von gebundenen Antikörpern erfolgt mit Hilfe von sekundären By way of example, "means for detecting the binding success" can be carried out by means of fluorescence labeling, biotinization, radio-isotopic labeling or colloidal gold or latex particle labeling in a customary manner Bound antibodies are made with the help of secondary antibodies
Antikörpern, die mit handelsüblichen Reportermolekülen Antibodies with commercial reporter molecules
markiert sind (z.B. Cy-, Alexa-, Dyomics, FITC- oder ähnliche Fluoreszenzfarbstoffe, kolloidale Gold- oder Latex-Partikel), oder mit Reporter-Enzymen wie alkalischer Phosphatase, (e.g., Cy, Alexa, Dyomics, FITC or similar fluorescent dyes, colloidal gold or latex particles), or with reporter enzymes such as alkaline phosphatase,
Meerrettichperoxidase, usw. und den entsprechenden Horseradish peroxidase, etc. and the corresponding
colorimetrischen, fluoreszenten oder chemolumineszenten colorimetric, fluorescent or chemiluminescent
Substraten. Eine Auslesung erfolgt z.B. mittels eines Substrates. A readout is e.g. by means of a
Microarray-Laserscanners , einer CCD-Kamera oder visuell. In einer weiteren Ausführungsform betrifft die Erfindung ein Arzneimittel / Wirkstoff oder Prodrug für Brustkrebs Microarray laser scanner, a CCD camera or visually. In another embodiment, the invention relates to a drug / prodrug or prodrug for breast cancer
entwickelt und erhältlich durch den Einsatz einer developed and available through the use of a
erfindungsgemäßen Brustkrebs-spezifischen Markersequenz, einer erfindungsgemäßen Anordnung, einer erfindungsgemäßen Breast cancer-specific marker sequence according to the invention, an inventive arrangement, an inventive
Verwendung, eines erfindungsgemäßen Assays. Use, of an assay according to the invention.
Gegenstand der Erfindung ist auch die Verwendung einer The invention is also the use of a
Brustkrebs-spezifischen Markersequenz ausgewählt aus Sequenzen SEQ ID o. 1 - 1473 und Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise mindestens 95 % der Länge von SEQ ID No . 1 - 1473 und Homologen von SEQ ID No . 1 - 1473 und deren Teilsequenzen mit einer Identität von mindestens 95 %, vorzugsweise mindestens 98 % oder mehr zu den Breast cancer-specific marker sequence selected from sequences SEQ ID No. 1 - 1473 and partial sequences from SEQ ID No. 1-1473 with at least 90%, preferably at least 95% of the length of SEQ ID No. 1 - 1473 and homologs of SEQ ID No. 1 - 1473 and their partial sequences with an identity of at least 95%, preferably at least 98% or more to the
entsprechenden Sequenzen und Proteinen/Peptiden kodiert durch die Sequenzen SEQ ID No. 1 - 491, kodiert durch deren corresponding sequences and proteins / peptides encoded by the sequences SEQ ID NO. 1 - 491, coded by the
Teilsequenzen und Homologen als Affinitätsmaterial zur Partial sequences and homologues as affinity material for
Durchführung einer Apherese oder Blutwäsche für Patienten mit Brustkrebs. Die Erfindung betrifft somit die Verwendung der erfindungsgemäßen Markersequenzen, vorzugsweise in Form einer Anordnung, als Affinitätsmaterial zur Durchführung einer  Performing an apheresis or blood wash for patients with breast cancer. The invention thus relates to the use of the marker sequences according to the invention, preferably in the form of an arrangement, as an affinity material for carrying out a
Blutwäsche im weiteren Sinne, wobei Substanzen aus Blood washing in a broader sense, taking substances out
Körperflüssigkeiten eines Patienten mit Brustkrebs, wie Blut oder Plasma, an die erfindungsgemäßen Markersequenzen binden und folglich der Körperflüssigkeit selektiv entzogen werden können . Body fluids of a patient with breast cancer, such as blood or plasma, bind to the marker sequences according to the invention and consequently can be selectively removed from the body fluid.
Die nachfolgenden Beispiele dienen der Erläuterung der The following examples serve to explain the
Erfindung ohne die Erfindung jedoch auf die Beispiele Invention without the invention, however, to the examples
einzuschränken . to restrict.
Die Durchführung der Beispiele erfolgt unter Verwendung der UNIarray Technologieplattform auf Basis quantitativer Analysen der Autoantikörperprofile im Serum von Brustkrebspatientinnen. Dadurch sollen systematisch Brustkrebs-assoziierte Antigene und Brustkrebs-assoziierte Autoantigene (Biomarker) The examples are performed using the UNIarray technology platform based on quantitative analysis of autoantibody profiles in breast cancer patients' serum. This is intended to systematically breast cancer-associated antigens and breast cancer-associated autoantigens (biomarkers)
identifiziert werden, die eine Früherkennung von Brustkrebs ermöglichen und/oder auf eine bestimmte Verlaufsform hindeuten (prognostische Relevanz). Beispiel 1 be identified that allow early detection of breast cancer and / or indicate a specific course (prognostic relevance). example 1
Zunächst erfolgt die Identifizierung von Kandidaten für First, the identification of candidates for
Brustkrebs-spezifische MarkerSequenzen . Breast cancer-specific marker sequences.
In der ersten Phase werden dazu 50 Serumproben von In the first phase, 50 serum samples of
Patientinnen mit Mammakarzinom auf einem MACROarray (umfasst etwa 10.000 unterschiedliche, rekombinante, humane Proteine) untersucht. Dabei werden Kandidaten für Brustkrebs-spezifische MarkerSequenzen identifiziert. Patients with breast cancer on a MACROarray (includes about 10,000 different, recombinant, human proteins) studied. Candidates for breast cancer-specific marker sequences are identified.
Beispiel 2 Example 2
In der anschließenden Testphase werden diese Kandidaten für Brustkrebs-spezifische Markersequenzen an Serumproben von 100 Brustkrebspatientinnen und 100 Patientinnen mit benignen In the subsequent test phase, these candidates will be selected for breast cancer-specific marker sequences on serum samples from 100 breast cancer patients and 100 benign women
Veränderungen der Brust bzw. 100 gesunden Kontroll- Patientinnen vergleichend analysiert und charakterisiert. Dadurch diese vergleichende Analyse werden vorwiegendChanges in the breast or 100 healthy control patients were comparatively analyzed and characterized. As a result, this comparative analysis will be predominantly
MarkerSequenzen identifiziert, die mit Brustkrebs-assoziiertenIdentified marker sequences associated with breast cancer
Autoantikörpern Wechselwirken. Autoantibodies interact.
Beispiel 3: Die Auswahl besonders signifikanter Biomarker (Brustkrebsspezifischer Markersequenzen) erfolgt mittels Example 3: The selection of particularly significant biomarkers (breast cancer-specific marker sequences) is carried out by means of
bioinformatischer Analyse. Die Kandidaten für Brustkrebsspezifische Markersequenzen werden dahingehend ausgewertet, ob sie zwischen verschiedenen Probanden (z.B. gesund/nicht gesund) /Patientengruppen (z.B. niedriges/hohes Risiko der Metastasenbildung) /Kohorten (z.B. bestimmte Vorgeschichte) diskriminieren . bioinformatic analysis. The candidates for breast cancer specific marker sequences are evaluated as discriminating between different subjects (e.g., healthy / unhealthy) / patient groups (e.g., low / high risk of metastasis) / cohorts (e.g., particular history).
Dazu werden die Markersequenzkandidaten auf einen Proteinarray aufgebracht und validiert. Die Datenauswertung erfolgt über statistische Analysen, beispielsweise Schwellenwertanalyse, Support Vector Machine Alogrithm (SVM). Der Probenverbrauch für die Validierung beträgt nur 50 μΐ / Probe. In einem ersten Ansatz werden auf diese Weise Kohorten der Kategorie I und II ausgewählt . Der erhaltene Proteinarray ist Brustkrebs spezifisch. Dieser Proteinarray umfasst ein oder mehrere Brustkrebs-spezifische MarkerSequenzen und erkennt Brustkrebs-assoziierte For this, the marker sequence candidates are applied to a protein array and validated. The data analysis is carried out via statistical analyzes, such as threshold value analysis, Support Vector Machine Alogrithm (SVM). The sample consumption for validation is only 50 μΐ / sample. In a first approach, cohorts of category I and II will be selected in this way. The resulting protein array is specific for breast cancer. This protein array includes one or more breast cancer-specific marker sequences and detects breast cancer-associated
Autoantikörper . Autoantibodies.
Kohorte I: Klinischer Befund Brustkrebs-positive Gruppe (CASE- Gruppe; verifiziert über histopathologischen Befund der Cohort I: Clinical findings Breast cancer positive group (CASE group, verified by histopathological findings of the
Biopsie) . Biopsy).
Kohorte II: Klinischer Befund Brustkrebs-negative Gruppe Cohort II: Clinical findings breast cancer negative group
(Kontroll-Gruppe) , Alters-gematched . Patientinnen werden ausgewählt nach Einschluß- und (Control group), age-matched. Patients are selected after inclusion and
Ausschlusskriterien exclusion criteria
Einschlußkriterien inclusion
Histologisch gesichertes Mammakarzinom - Histologisch gesicherte, nicht-neoplastische Veränderung Histologically proven breast cancer - Histologically proven, non-neoplastic change
Gesunde altersgematchte Kontrolle Healthy age-matched control
Zum Zeitpunkt der Diagnose (vor der Operation) At the time of diagnosis (before surgery)
- Vor bzw. während neoad uvanter und adjuvanter - Before or during neoad uvanter and adjuvant
Antiöstrogentherapie, adjuvanter Chemotherapie oder adjuvanter Aromataseinhibitortherapie . Anti-estrogen therapy, adjuvant chemotherapy or adjuvant aromatase inhibitor therapy.
Ausschlusskriterien exclusion criteria
Alter unter 18 Jahren Age under 18 years
Bereits erfolgte Tumorbehandlung Already done tumor treatment
Entsprechende Proteinarrays werden für Diagnose, Voraussage des Therapieverlaufs und Vorhersage der Metastasenbildung entwickelt . Corresponding protein arrays are being developed for diagnosis, predicting the course of therapy, and predicting metastasis.
Beispiel 4: Example 4:
Für die Entwicklung eines Proteinarrays für die Diagnose von Brustkrebs, werden die Ergebnisse der Autoantikörperanalyse mit dem goldenen Standard der Diagnose verglichen und die identifizierten Markersequenzen werden validiert (Brustkrebsspezifische MarkerSequenzen ; Markersequenzen für Brustkrebs) . Die Ergebnisse werden dann mit anderen klinischen For the development of a protein array for the diagnosis of breast cancer, the results of the autoantibody analysis are compared with the golden standard of diagnosis and the identified marker sequences are validated (breast cancer specific marker sequences, marker sequences for breast cancer). The results will then be compared with other clinical
Charakteristika von Brustkrebs, beispielsweise Tumorgröße und Malignität korreliert. Beispiel 5: Characteristics of breast cancer, such as tumor size and malignancy correlated. Example 5:
Bei der Entwicklung eines Proteinarrays zur Voraussage des Therapieverlaufs wird ein bestimmtes Autoantikörperprofil bzw. ein bestimmtes Signal des Proteinarrays mit dem Ansprechen des Brustkrebses auf eine bestimmte Therapie korreliert. Darüber hinaus werden Änderungen des Autoantikörperprofils validiert - auch bezüglich verschiedener Behandlungsoptionen (Continuous time modelling) . In developing a protein array to predict the course of therapy, a particular autoantibody profile or signal of the protein array is correlated with the response of breast cancer to a particular therapy. In addition, changes in the autoantibody profile are validated, including with regard to various treatment options (continuous-time modeling).
Beispiel 6: Bei der Entwicklung eines Proteinarrays für die Prädiktion der Metastasenbildung werden Brustkrebs-spezifische Example 6: In the development of a protein array for the prediction of metastasis formation, breast cancer specific
Markersequenzen ausgewählt, die mit Brustkrebs-assoziierten Autoantikörpern wechselwirken, die als Indikator für Marker sequences that interact with breast cancer-associated autoantibodies, which are used as an indicator of
Metastasenbildung geeignet sind. Durch den Vergleich von Metastasis are suitable. By comparing
Autoantikörpern zum Zeitpunkt der Diagnose von Patientinnen mit und ohne Metastasenbildung können Patientinnen Autoantibodies at the time of diagnosis of patients with and without metastasis can patients
identifiziert werden, die ein hohes Metastaserisiko haben. be identified, which have a high metastasis risk.
Im Rahmen der Identifizierung und Validierung von Brustkrebsspezifischen Markersequenzen können bioinformatische Analysen durchgeführt werden. Für jedes Serum können dazu mittels Bioinformatic analyzes can be performed as part of the identification and validation of breast cancer specific marker sequences. For each serum can do so by means of
Microarray Reaktivitäten gegen ca. 2000 unterschiedliche Microarray reactivities against about 2000 different
Antigene gemessen werden. Diese Daten werden für ein Ranking der gespotteten Antigene bzgl. ihrer Differenzierungsfähigkeit zwischen gesunden und erkrankten Seren benutzt. Diese Antigens are measured. These data are used to rank the spotted antigens for their ability to differentiate between healthy and diseased sera. These
Auswertung kann mittels des nicht parametrischen Mann-Whitney Tests auf normalisierten Intensitätsdaten durchgeführt werden. Zur Normalisierung wird ein interner Standard benutzt, der auf jedem Proteinarray mitgespottet wird. Da für jedes Antigen ein p-Wert berechnet wird, werden Methoden zur Korrektur des multiples Testens eingesetzt. Als sehr konservativer Ansatz wird eine Bonferroni Korrektur durchgeführt und zusätzlich wird die weniger restriktive False Discovery Rate (FDR) nach Benjamini & Hochberg berechnet. Evaluation can be performed on normalized intensity data using the non-parametric Mann-Whitney test. For normalization, an internal standard is used that is spotted on each protein array. Since a p-value is calculated for each antigen, methods for correcting the multiple testing are used. As a very conservative approach a Bonferroni correction is performed and in addition the less restrictive False Discovery Rate (FDR) according to Benjamini & Hochberg is calculated.
Desweiteren werden die Daten zur Klassifikation der Seren benutzt. Hierbei kommen unterschiedliche multivariate Methoden zum Einsatz. Dies sind Methoden aus den statistischen Furthermore, the data are used to classify the sera. Here, different multivariate methods are used. These are methods from the statistical
Lernverfahren wie Support Vector Machines (SVM), Neuronale Netze oder Klassifikationsbäume, sowie eine Learning methods such as support vector machines (SVM), neural networks or classification trees, as well as a
Schwellenwertmethode, welche sowohl zur Klassifikation als auch zur visuellen Repräsentation der Daten geeignet ist.  Threshold method, which is suitable for both classification and visual representation of the data.
Zur Vermeidung von Overfitting wird beispielsweise eine lOfache Cross-Validierung der Daten durchgeführt. To avoid overfitting, for example, a 10-fold cross-validation of the data is performed.
Die erfindungsgermäßen Sequenzen sind im anliegenden Sequenzprotokoll aufgeführt. Die Klonsequenzen (cDNA) SEQ ID No. 1 - 491, die RNA Sequenzen SEQ ID. No . 492 - 982 und die Proteinsequenzen SEQ ID No . 983 - 1473) . The erfindungsgermäßen sequences are listed in the attached sequence listing. The clone sequences (cDNA) SEQ ID no. 1-491, the RNA sequences SEQ ID. No. 492-982 and the protein sequences SEQ ID No. 983 - 1473).
Tabelle A: Daten zu Brustkrebs-spezifischen Markersequenzen (RNA) SEQ ID No . 492 - 982 Table A: Data on breast cancer specific marker sequences (RNA) SEQ ID No. 492 - 982
SEQ Accession Alias Blast SEQ Accession Alias Blast
ID No . Accession No . ID No. Accession No.
No . No.
492 gi 1261337182 NM_182905.4 WAS protein family homolog 1  492 gi 1261337182 NM_182905.4 WHAT protein family homolog 1
[Homo sapiens]  [Homo sapiens]
493 gi 116877437 BC016965.1 NLRP1 protein [Homo sapiens] 493 gi 116877437 BC016965.1 NLRP1 protein [Homo sapiens]
494 gi 157242760 NM_003804.3 receptor-interacting 494 gi 157242760 NM_003804.3 receptor-interacting
serine/threonine-protein kinase 1 [Homo sapiens]  serine / threonine protein kinase 1 [Homo sapiens]
495 gi 1225579068 NM_012426.4 splicing factor 3B subunit 3  495 gi 1225579068 NM_012426.4 splicing factor 3B subunit 3
[Homo sapiens] 496 gi 1221136896 NM_014786.3 rho guanine nucleotide [Homo sapiens] 496 gi 1221136896 NM_014786.3 rho guanine nucleotide
exchange factor 17 [Homo sapiens ]  exchange factor 17 [Homo sapiens]
497 gi 160218896 NM_005748.3 YYl-associated factor 2  497 gi 160218896 NM_005748.3 YYl-associated factor 2
isoform 2 [Homo sapiens] isoform 2 [Homo sapiens]
498 gi 1157388905 NM_017806.2 lck-interacting transmembrane adapter 1 [Homo sapiens]498 gi 1157388905 NM_017806.2 Lck-interacting transmembrane adapter 1 [Homo sapiens]
499 gi 113569955 NM_030978.1 actin-related protein 2/3 499 gi 113569955 NM_030978.1 actin-related protein 2/3
complex subunit 5-like protein [Homo sapiens]  complex subunit 5-like protein [Homo sapiens]
500 gi 117933771 NM_080388.1 protein S100-A16 [Homo  500 gi 117933771 NM_080388.1 protein S100-A16 [homo
sapiens ]  sapiens]
501 gi 1171906614 NM_006891.3 gamma-crystallin D [Homo  501 gi 1171906614 NM_006891.3 gamma-crystallin D [Homo
sapiens ]  sapiens]
502 gi 1157389013 NM_001408.2 Cadherin EGF LAG seven-pass G- type receptor 2 precursor  502 gi 1157389013 NM_001408.2 Cadherin EGF LAG seven-pass G-type receptor 2 precursor
[Homo sapiens]  [Homo sapiens]
503 gi 155956909 NM_002430.2 probable tumor suppressor  503 gi 155956909 NM_002430.2 probable tumor suppressor
protein MN1 [Homo sapiens] protein MN1 [Homo sapiens]
504 gi 121396481 NM_003512.3 histone H2A type 1-C [Homo sapiens ] 504 gi 121396481 NM_003512.3 histone H2A type 1-C [Homo sapiens]
505 gi 177812677 NM_006903.4 inorganic pyrophosphatase 2, mitochondrial isoform 2 precursor [Homo sapiens] 505 gi 177812677 NM_006903.4 inorganic pyrophosphatase 2, mitochondrial isoform 2 precursor [Homo sapiens]
506 gi 141349492 NM_013239.3 serine/threonine-protein 506 gi 141349492 NM_013239.3 serine / threonine protein
Phosphatase 2A regulatory subunit B' ' subunit beta [Homo sapiens ]  Phosphatase 2A regulatory subunit B '' subunit beta [Homo sapiens]
507 gi 156118233 NM_181716.2 centromere protein V [Homo sapiens ]  507 gi 156118233 NM_181716.2 centromere protein V [Homo sapiens]
508 gi 1225579128 NM_001018024.2 mature T-cell proliferation 1 neighbor protein [Homo 508 gi 1225579128 NM_001018024.2 mature T-cell proliferation 1 neighbor protein [Homo
sapiens ]  sapiens]
509 gi 1334085246 NM_014889.3 presequence protease,  509 gi 1334085246 NM_014889.3 presequence protease,
mitochondrial isoform 2 precursor [Homo sapiens] mitochondrial isoform 2 precursor [Homo sapiens]
510 gi 166932989 NM_001018078.1 folylpolyglutamate synthase, mitochondrial isoform b [Homo sapiens ] 510 gi 166932989 NM_001018078.1 folylpolyglutamate synthase, mitochondrial isoform b [Homo sapiens]
511 gi 131317296 NM_181353.1 DNA-binding protein inhibitor  511 gi 131317296 NM_181353.1 DNA-binding protein inhibitor
ID-1 isoform b [Homo sapiens] ID-1 isoform b [Homo sapiens]
512 gi 1209413724 NM_003692.3 tomoregulin-1 precursor [Homo sapiens ] 512 gi 1209413724 NM_003692.3 Tomoregulin-1 precursor [Homo sapiens]
513 gi 137181353 AY358124.1 SEMA5B [Homo sapiens]  513 gi 137181353 AY358124.1 SEMA5B [Homo sapiens]
514 gi 121704284 NM_021219.2 junctional adhesion molecule B precursor [Homo sapiens] 514 gi 121704284 NM_021219.2 junctional adhesion molecule B precursor [Homo sapiens]
515 gi 1254028259 NM_182501.3 mTERF domain-containing 515 gi 1254028259 NM_182501.3 mTERF domain-containing
protein 2 [Homo sapiens] protein 2 [Homo sapiens]
516 gi 1161016768 NM_001799.3 cyclin-dependent kinase 7 516 gi 1161016768 NM_001799.3 cyclin-dependent kinase 7
[Homo sapiens]  [Homo sapiens]
517 gi 1180636 M93008.1 L-isoaspartyl/D-aspartyl  517 gi 1180636 M93008.1 L-isoaspartyl / D-aspartyl
protein carboxyl  protein carboxyl
methyltransferase [Homo sapiens ]  methyltransferase [Homo sapiens]
518 gi 167782361 NM_019030.2 ATP-dependent RNA helicase  518 gi 167782361 NM_019030.2 ATP-dependent RNA helicase
DHX29 [Homo sapiens]  DHX29 [Homo sapiens]
519 gi 114195613 NM_018940.2 protocadherin beta-7 precursor  519 gi 114195613 NM_018940.2 protocadherin beta-7 precursor
[Homo sapiens]  [Homo sapiens]
520 gi 193204870 NM_021229.3 netrin-4 precursor [Homo  520 gi 193204870 NM_021229.3 netrin-4 precursor [Homo
sapiens ]  sapiens]
521 gi 1224967099 NM_001734.3 complement Cls subcomponent precursor [Homo sapiens] 522 gi 116507949 NM_014466.2 tektin-2 [Homo sapiens] 521 gi 1224967099 NM_001734.3 complement Cls subcomponent precursor [Homo sapiens] 522 gi 116507949 NM_014466.2 tectin-2 [Homo sapiens]
523 gi 175750475 NM_001033566.1 mitochondrial Rho GTPase 1 isoform 2 [Homo sapiens] 523 gi 175750475 NM_001033566.1 mitochondrial Rho GTPase 1 isoform 2 [Homo sapiens]
524 gi 1216548626 NM_001142467.1 transcription factor HES-4 isoform 1 [Homo sapiens]524 g1 1216548626 NM_001142467.1 transcription factor HES-4 isoform 1 [Homo sapiens]
525 gi 138683798 NM_033121.1 ankyrin repeat domain- containing protein 13A [Homo sapiens ] 525 gi 138683798 NM_033121.1 ankyrin repeat domain-containing protein 13A [Homo sapiens]
526 gi 1285002230 NM_001083112.2 glycerol-3-phosphate  526 gi 1285002230 NM_001083112.2 glycerol-3-phosphate
dehydrogenase, mitochondrial precursor [Homo sapiens] dehydrogenase, mitochondrial precursor [Homo sapiens]
527 gi 15454057 NM_006278.1 CMP-N-acetylneuraminate-beta- galactosamide-alpha-2 , 3- sialyltransferase 4 [Homo sapiens ] 527 gi 15454057 NM_006278.1 CMP-N-acetylneuraminate-beta-galactosamide-alpha-2, 3-sialyltransferase 4 [Homo sapiens]
528 gi 1169259774 NM_014737.2 ras association domain- containing protein 2 [Homo sapiens ]  528 gi 1169259774 NM_014737.2 ras association domain-containing protein 2 [Homo sapiens]
529 gi 1126091094 NM_001081563.1 myotonin-protein kinase  529 gi 1126091094 NM_001081563.1 myotonin protein kinase
isoform 1 [Homo sapiens] isoform 1 [Homo sapiens]
530 gi 1194097397 NM_002841.3 receptor-type tyrosine-protein 530 gi 1194097397 NM_002841.3 receptor-type tyrosine protein
Phosphatase gamma precursor [Homo sapiens]  Phosphatase gamma precursor [Homo sapiens]
531 gi 141350325 NM_003791.2 membrane-bound transcription factor site-1 protease  531 gi 141350325 NM_003791.2 membrane-bound transcription factor site-1 protease
preproprotein [Homo sapiens] preproprotein [Homo sapiens]
532 gi 184508630 NM_024419.3 CDP-diacylglycerol--glycerol- 3-phosphate 3- phosphatidyltransferase, mitochondrial precursor [Homo sapiens ] 533 gi 1187960072 NM_006341.3 mitotic spindle assembly 532 gi 184508630 NM_024419.3 CDP-diacylglycerol-glycerol-3-phosphate-3-phosphatidyltransferase, mitochondrial precursor [Homo sapiens] 533 gi 1187960072 NM_006341.3 mitotic spindle assembly
Checkpoint protein MAD2B [Homo sapiens ]  Checkpoint protein MAD2B [Homo sapiens]
534 gi 176563938 NM_015920.3 40S ribosomal protein S27-like  534 gi 176563938 NM_015920.3 40S ribosomal protein S27-like
[Homo sapiens]  [Homo sapiens]
535 gi 1169234806 NM_015401.3 histone deacetylase 7 isoform a [Homo sapiens]  535 gi 1169234806 NM_015401.3 histone deacetylase 7 isoform a [Homo sapiens]
536 gi 1120952828 NM_001079906.1 zinc finger protein 331 [Homo sapiens ]  536 gi 1120952828 NM_001079906.1 zinc finger protein 331 [Homo sapiens]
537 gi 157222569 NM_138477.2 codanin-1 [Homo sapiens] 537 gi 157222569 NM_138477.2 codanin-1 [Homo sapiens]
538 gi 121361096 NM_004125.2 DNAJC25-GNG10 protein [Homo sapiens ] 538 gi 121361096 NM_004125.2 DNAJC25-GNG10 protein [Homo sapiens]
539 gi 151093843 NM_004147.3 developmentally-regulated GTP- binding protein 1 [Homo sapiens ]  539 gi 151093843 NM_004147.3 developmentally-regulated GTP-binding protein 1 [Homo sapiens]
540 gi 1221316745 NM_003156.3 stromal interaction molecule 1 precursor [Homo sapiens] 540 gi 1221316745 NM_003156.3 stromal interaction molecule 1 precursor [Homo sapiens]
541 gi 1327365362 NM_203290.2 DNA-directed RNA polymerases I and III subunit RPAC1 [Homo sapiens ] 541 gi 1327365362 NM_203290.2 DNA-directed RNA polymerases I and III subunit RPAC1 [Homo sapiens]
542 gi 1114520590 NM_032985.4 protein transport protein  542 gi 1114520590 NM_032985.4 protein transport protein
Sec23B isoform 1 [Homo  Sec23B isoform 1 [Homo
sapiens ]  sapiens]
543 gi 1194018465 NM_004454.2 ETS translocation variant 5  543 gi 1194018465 NM_004454.2 ETS translocation variant 5
[Homo sapiens]  [Homo sapiens]
544 gi 162953137 NM_002192.2 inhibin beta A chain precursor  544 gi 162953137 NM_002192.2 inhibin beta A chain precursor
[Homo sapiens]  [Homo sapiens]
545 gi 131652260 NM_002466.2 myb-related protein B [Homo sapiens ]  545 gi 131652260 NM_002466.2 myb-related protein B [Homo sapiens]
546 gi 185680425 DQ335454.1 BS69 variant 3 [Homo sapiens] 546 gi 185680425 DQ335454.1 BS69 variant 3 [Homo sapiens]
547 gi 1218563704 NM_025193.3 3 beta-hydroxysteroid dehydrogenase type 7 isoform a 547 gi 1218563704 NM_025193.3 3 beta-hydroxysteroid dehydrogenase type 7 isoform a
[Homo sapiens]  [Homo sapiens]
548 gi 1164419759 NM_000107.2 DNA damage-binding protein 2  548 gi 1164419759 NM_000107.2 DNA damage-binding protein 2
[Homo sapiens]  [Homo sapiens]
549 gi 1114155138 NM_153649.3 tropomyosin alpha-3 chain  549 gi 1114155138 NM_153649.3 tropomyosin alpha-3 chain
isoform 2 [Homo sapiens] isoform 2 [Homo sapiens]
550 gi 1215820618 NM_014699.3 zinc finger protein 646 [Homo sapiens ] 550 gi 1215820618 NM_014699.3 zinc finger protein 646 [Homo sapiens]
551 gi 1157502196 NM_014738.4 hypothetical protein LOC9772  551 gi 1157502196 NM_014738.4 hypothetical protein LOC9772
[Homo sapiens]  [Homo sapiens]
552 gi 158331162 NM_001009936.1 PHD finger protein 19 isoform b [Homo sapiens]  552 gi 158331162 NM_001009936.1 PHD finger protein 19 isoform b [Homo sapiens]
553 gi 1110611232 NM_130445.2 collagen alpha-1 (XVIII ) chain isoform 2 precursor [Homo sapiens ]  553 gi 1110611232 NM_130445.2 collagen alpha-1 (XVIII) chain isoform 2 precursor [Homo sapiens]
554 gi 123110958 NM_000396.2 cathepsin K preproprotein  554 gi 123110958 NM_000396.2 cathepsin K preproprotein
[Homo sapiens]  [Homo sapiens]
555 gi 1150417970 NM_003174.3 supervillin isoform 1 [Homo sapiens ]  555 gi 1150417970 NM_003174.3 supervillin isoform 1 [Homo sapiens]
556 gi 184872172 NM_003432.1 zinc finger protein 131 [Homo sapiens ]  556 gi 184872172 NM_003432.1 zinc finger protein 131 [Homo sapiens]
557 gi 154792739 NM_014858.2 transmembrane and coiled-coil domains protein 2 isoform 1 [Homo sapiens]  557 gi 154792739 NM_014858.2 transmembrane and coiled-coil domains protein 2 isoform 1 [Homo sapiens]
558 gi 114589877 NM_005864.2 embryonal Fyn-associated  558 gi 114589877 NM_005864.2 embryonic Fyn-associated
Substrate isoform 1 [Homo sapiens ]  Substrates isoform 1 [Homo sapiens]
559 gi 1148529010 NM_006091.3 coronin-2B isoform 1 [Homo sapiens ]  559 gi 1148529010 NM_006091.3 coronin-2B isoform 1 [Homo sapiens]
560 gi 151317348 NM_001003789.1 rab-like protein 2B isoform 1  560 gi 151317348 NM_001003789.1 rab-like protein 2B isoform 1
[Homo sapiens] 561 gi 1119120893 NM_015263.2 dmX-like protein 2 isoform 2 [Homo sapiens] 561 gi 1119120893 NM_015263.2 dmX-like protein 2 isoform 2
[Homo sapiens]  [Homo sapiens]
562 gi 1213972618 NM_001141973.1 probable cation-transporting  562 gi 1213972618 NM_001141973.1 probable cation-transporting
ATPase 13A2 isoform 2 [Homo sapiens ]  ATPase 13A2 isoform 2 [Homo sapiens]
563 gi 1283135239 NM_020155.3 integral membrane protein  563 gi 1283135239 NM_020155.3 integral membrane protein
GPR137 isoform 3 [Homo  GPR137 isoform 3 [Homo
sapiens ]  sapiens]
564 gi 1164565439 NM_024571.3 U11/U12 small nuclear  564 gi 1164565439 NM_024571.3 U11 / U12 small nuclear
ribonucleoprotein 25 kDa protein [Homo sapiens]  ribonucleoprotein 25 kDa protein [Homo sapiens]
565 gi 145331214 NM_032429.1 leucine zipper putative tumor suppressor 2 [Homo sapiens] 565 gi 145331214 NM_032429.1 leucine zipper putative tumor suppressor 2 [Homo sapiens]
566 gi 194721260 NM_033133.4 2 ' , 3 ' -cyclic-nucleotide 3'- phosphodiesterase [Homo sapiens ] 566 gi 194721260 NM_033133.4 2 ', 3' cyclic nucleotide 3'-phosphodiesterase [Homo sapiens]
567 gi 1115511050 NM_002095.4 transcription initiation  567 gi 1115511050 NM_002095.4 transcription initiation
factor IIE subunit beta [Homo sapiens ]  factor II subunit beta [Homo sapiens]
568 gi 1156616274 NM_002691.2 DNA Polymerase delta catalytic subunit [Homo sapiens]  568 gi 1156616274 NM_002691.2 DNA polymerase delta catalytic subunit [Homo sapiens]
569 gi 138146093 NM_005481.2 mediator of RNA Polymerase II transcription subunit 16 [Homo sapiens ]  569 gi 138146093 NM_005481.2 mediator of RNA polymerase II transcription subunit 16 [Homo sapiens]
570 gi 145597176 NM_015043.3 TBCl domain family member 9B isoform b [Homo sapiens] 570 gi 145597176 NM_015043.3 TBCl domain family member 9B isoform b [Homo sapiens]
571 gi 123238252 NM_004377.2 carnitine 0- palmitoyltransferase 1, muscle isoform isoform a [Homo sapiens ] 571 gi 123238252 NM_004377.2 carnitine 0-palmitoyltransferase 1, muscle isoform isoform a [Homo sapiens]
572 gi 198986448 NM_000496.2 beta-crystallin B2 [Homo sapiens ] 572 gi 198986448 NM_000496.2 beta-crystallin B2 [Homo sapiens]
573 gi 14505784 NM_000294.1 Phosphorylase b kinase gamma catalytic chain, testis/liver isoform isoform 1 [Homo sapiens ]  573 gi 14505784 NM_000294.1 Phosphorylase b kinase gamma catalytic chain, testis / liver isoform isoform 1 [Homo sapiens]
574 gi 178482607 NM_021129.3 inorganic pyrophosphatase  574 gi 178482607 NM_021129.3 inorganic pyrophosphatase
[Homo sapiens]  [Homo sapiens]
575 gi 118027315 AF289556.1 unknown [Homo sapiens]  575 gi 118027315 AF289556.1 unknown [Homo sapiens]
576 gi 155770885 NM_006537.2 ubiquitin carboxyl-terminal hydrolase 3 [Homo sapiens] 576 gi 155770885 NM_006537.2 ubiquitin carboxyl-terminal hydrolase 3 [Homo sapiens]
577 gi 159710102 NM_006315.4 polycomb group RING finger protein 3 [Homo sapiens]577 gi 159710102 NM_006315.4 polycomb group RING finger protein 3 [Homo sapiens]
578 gi 12224666 AB002361.1 KIAA0363 [Homo sapiens]578 gi 12224666 AB002361.1 KIAA0363 [Homo sapiens]
579 gi 133356549 NM_182679.1 G patch domain-containing protein 4 isoform 2 [Homo sapiens ] 579 gi 133356549 NM_182679.1 G patch domain-containing protein 4 isoform 2 [Homo sapiens]
580 gi 1210147473 NM_022366.2 dimethyladenosine transferase  580 gi 1210147473 NM_022366.2 dimethyladenosine transferase
2, mitochondrial [Homo sapiens ]  2, mitochondrial [Homo sapiens]
581 gi 150346003 NM_002626.4 6-phosphofructokinase, liver type [Homo sapiens]  581 gi 150346003 NM_002626.4 6-phosphofructokinase, liver type [Homo sapiens]
582 gi 1187828433 NM_006224.3 phosphatidylinositol transfer protein alpha isoform [Homo sapiens ]  582 gi 1187828433 NM_006224.3 phosphatidylinositol transfer protein alpha isoform [Homo sapiens]
583 gi 153749664 NM_005654.4 COUP transcription factor 1  583 gi 153749664 NM_005654.4 COUP transcription factor 1
[Homo sapiens]  [Homo sapiens]
584 gi 134485712 NM_004663.3 ras-related protein Rab-llA isoform 1 [Homo sapiens] 584 gi 134485712 NM_004663.3 ras-related protein Rab-IIA isoform 1 [Homo sapiens]
585 gi 1150378438 NM_020226.3 PR domain zinc finger protein 585 gi 1150378438 NM_020226.3 PR domain zinc finger protein
8 [Homo sapiens]  8 [Homo sapiens]
586 gi 152694663 NM_020799.2 AMSH-like protease [Homo sapiens ] 586 gi 152694663 NM_020799.2 AMSH-like protease [Homo sapiens]
587 gi 1169646771 NM_002064.2 glutaredoxin-1 [Homo sapiens] 587 gi 1169646771 NM_002064.2 glutaredoxin-1 [Homo sapiens]
588 gi 1209969817 NM_001540.3 heat shock protein beta-1 588 gi 1209969817 NM_001540.3 heat shock protein beta-1
[Homo sapiens]  [Homo sapiens]
589 gi 1164664491 NM_007103.3 NADH dehydrogenase  589 gi 1164664491 NM_007103.3 NADH dehydrogenase
[ubiquinone] flavoprotein 1, mitochondrial isoform 1 precursor [Homo sapiens] [ubiquinone] flavoprotein 1, mitochondrial isoform 1 precursor [Homo sapiens]
590 gi 148255923 NM_021075.3 NADH dehydrogenase 590 gi 148255923 NM_021075.3 NADH dehydrogenase
[ubiquinone] flavoprotein 3, mitochondrial isoform a precursor [Homo sapiens] [ubiquinone] flavoprotein 3, mitochondrial isoform a precursor [Homo sapiens]
591 gi 18923891 NM_018663.1 peroxisomal membrane protein 2 591 gi 18923891 NM_018663.1 peroxisomal membrane protein 2
[Homo sapiens]  [Homo sapiens]
592 gi 1117553583 NM_001077523.1 AP-3 complex subunit delta-1 isoform 1 [Homo sapiens] 592 gi 1117553583 NM_001077523.1 AP-3 complex subunit delta-1 isoform 1 [Homo sapiens]
593 gi 1119393885 NM_014706.3 squamous cell Carcinoma 593 gi 1119393885 NM_014706.3 squamous cell carcinoma
antigen recognized by T-cells 3 [Homo sapiens]  antigen recognized by T-cells 3 [Homo sapiens]
594 gi 126787964 NM_006411.2 l-acyl-sn-glycerol-3-phosphate acyltransferase alpha [Homo sapiens ]  594 gi 126787964 NM_006411.2 l-acyl-sn-glycerol-3-phosphate acyltransferase alpha [Homo sapiens]
595 gi 110947033 NM_006454.2 max dimerization protein 4  595 gi 110947033 NM_006454.2 max dimerization protein 4
[Homo sapiens]  [Homo sapiens]
596 gi 1187960089 NM_015327.2 protein SMG5 [Homo sapiens] 596 gi 1187960089 NM_015327.2 protein SMG5 [Homo sapiens]
597 gi 1141801721 NM_015153.2 PHD finger protein 3 [Homo 597 gi 1141801721 NM_015153.2 PHD finger protein 3 [Homo
sapiens ]  sapiens]
598 gi 1187761372 NM_005744.3 E3 ubiquitin-protein ligase  598 gi 1187761372 NM_005744.3 E3 ubiquitin protein ligase
ARIH1 [Homo sapiens]  ARIH1 [Homo sapiens]
599 gi 1102467483 NM_017751.2 sphingomyelin  599 gi 1102467483 NM_017751.2 sphingomyelin
Phosphodiesterase 4 isoform 1 [Homo sapiens] Phosphodiesterase 4 isoform 1 [Homo sapiens]
600 gi 131543086 NM_020147.2 THAP domain-containing protein  600 gi 131543086 NM_020147.2 THAP domain-containing protein
10 [Homo sapiens]  10 [Homo sapiens]
601 gi 1214010239 NM_001142292.1 VIP36-like protein isoform 1  601 gi 1214010239 NM_001142292.1 VIP36-like protein isoform 1
[Homo sapiens]  [Homo sapiens]
602 gi 142476160 NM_032902.5 protein Phosphatase 1  602 gi 142476160 NM_032902.5 protein phosphatase 1
regulatory subunit 16A [Homo sapiens ]  regulatory subunit 16A [Homo sapiens]
603 gi 1333609250 NM_001005850.2 zinc finger protein 835 [Homo sapiens ]  603 gi 1333609250 NM_001005850.2 zinc finger protein 835 [Homo sapiens]
604 gi 1189011564 NM_000038.4 adenomatous Polyposis coli protein isoform b [Homo sapiens ]  604 gi 1189011564 NM_000038.4 adenomatous polyposis coli protein isoform b [Homo sapiens]
605 gi 187578391 NM_031845.2 microtubule-associated protein  605 gi 187578391 NM_031845.2 microtubule-associated protein
2 isoform 2 [Homo sapiens] 2 isoform 2 [Homo sapiens]
606 gi 119913344 NM_006527.2 histone RNA hairpin-binding protein [Homo sapiens] 606 gi 119913344 NM_006527.2 histone RNA hairpin-binding protein [Homo sapiens]
607 gi 1110225356 NM_006819.2 stress-induced-phosphoprotein  607 gi 1110225356 NM_006819.2 stress-induced phosphoprotein
1 [Homo sapiens]  1 [Homo sapiens]
608 gi 142544225 NM_020857.2 vacuolar protein sorting- associated protein 18 homolog [Homo sapiens]  608 gi 142544225 NM_020857.2 vacuolar protein sorting-associated protein 18 homolog [Homo sapiens]
609 gi 1166795298 NM_006516.2 solute carrier family 2,  609 gi 1166795298 NM_006516.2 solute carrier family 2,
facilitated glucose  facilitated glucose
transporter member 1 [Homo sapiens ]  transporter member 1 [Homo sapiens]
610 gi 1211904132 NM_014764.3 DAZ-associated protein 2  610 gi 1211904132 NM_014764.3 DAZ-associated protein 2
isoform a [Homo sapiens] isoform a [Homo sapiens]
611 gi 1148612828 NM_001098509.1 small G protein signaling 611 gi 1148612828 NM_001098509.1 small G protein signaling
modulator 2 isoform 2 [Homo sapiens ] 612 gi 140018634 NM_015440.3 monofunctional Cl- tetrahydrofolate synthase, mitochondrial isoform 2 precursor [Homo sapiens]modulator 2 isoform 2 [Homo sapiens] 612 gi 140018634 NM_015440.3 monofunctional C-tetrahydrofolate synthase, mitochondrial isoform 2 precursor [Homo sapiens]
613 gi 1169234785 NM_017991.4 hypothetical protein LOC55683 isoform b [Homo sapiens]613 gi 1169234785 NM_017991.4 hypothetical protein LOC55683 isoform b [Homo sapiens]
614 gi 170778868 NM_021933.2 migration and invasion- inhibitory protein [Homo sapiens ] 614 gi 170778868 NM_021933.2 migration and invasion- inhibitory protein [Homo sapiens]
615 gi 1113204623 NM_032193.3 ribonuclease H2 subunit C  615 gi 1113204623 NM_032193.3 ribonuclease H2 subunit C
[Homo sapiens]  [Homo sapiens]
616 gi 165301131 NM_138338.2 DNA-directed RNA Polymerase  616 gi 165301131 NM_138338.2 DNA-directed RNA polymerase
III subunit RPC8 isoform a [Homo sapiens]  III subunit RPC8 isoform a [Homo sapiens]
617 gi 1221219069 NM_145295.3 zinc finger protein 627 [Homo sapiens ]  617 gi 1221219069 NM_145295.3 zinc finger protein 627 [Homo sapiens]
618 gi 121264342 NM_002967.2 scaffold attachment factor Bl isoform 3 [Homo sapiens] 618 gi 121264342 NM_002967.2 scaffold attachment factor Bl isoform 3 [Homo sapiens]
619 gi 1197085592 NM_006328.3 RNA-binding protein 14 isoform 619 gi 1197085592 NM_006328.3 RNA-binding protein 14 isoform
1 [Homo sapiens]  1 [Homo sapiens]
620 gi 1149588533 NM_001098833.1 ataxin-7-like protein 3  620 gi 1149588533 NM_001098833.1 ataxin-7-like protein 3
isoform b [Homo sapiens] isoform b [Homo sapiens]
621 gi 120270356 NM_138802.1 ANl-type zinc finger protein 621 gi 120270356 NM_138802.1 ANl-type zinc finger protein
2B [Homo sapiens]  2B [Homo sapiens]
622 gi 135493700 NM_152564.3 vacuolar protein sorting- associated protein 13B isoform 1 [Homo sapiens]  622 gi 135493700 NM_152564.3 vacuolar protein sorting-associated protein 13B isoform 1 [Homo sapiens]
623 gi 1142385096 NM_001077693.2 endothelial cell-specific  623 gi 1142385096 NM_001077693.2 endothelial cell-specific
Chemotaxis regulator precursor [Homo sapiens]  Chemotaxis regulator precursor [Homo sapiens]
624 gi 171773207 NM_000683.3 alpha-2C adrenergic receptor [Homo sapiens] 624 gi 171773207 NM_000683.3 alpha-2C adrenergic receptor [Homo sapiens]
625 gi 155925575 NM_000597.2 insulin-like growth factor- binding protein 2 precursor [Homo sapiens]  625 gi 155925575 NM_000597.2 insulin-like growth factor-binding protein 2 precursor [Homo sapiens]
626 gi 171772582 NM_001030001.1 40S ribosomal protein S29  626 gi 171772582 NM_001030001.1 40S ribosomal protein S29
isoform 2 [Homo sapiens] isoform 2 [Homo sapiens]
627 gi 118105053 NM_014970.2 kinesin-associated protein 3 isoform 1 [Homo sapiens]627 gi 118105053 NM_014970.2 kinesin-associated protein 3 isoform 1 [Homo sapiens]
628 gi 134147578 NM_014338.3 phosphatidylserine 628 gi 134147578 NM_014338.3 phosphatidylserines
decarboxylase proenzyme [Homo sapiens ]  decarboxylase proenzymes [Homo sapiens]
629 gi 112060856 AF308303.1 serologically defined breast  629 gi 112060856 AF308303.1 serologically defined breast
Cancer antigen NY-BR-99 [Homo sapiens ]  Cancer antigen NY-BR-99 [Homo sapiens]
630 gi 17020624 AK000496.1 unnamed protein product [Homo sapiens ]  630 gi 17020624 AK000496.1 unnamed protein product [Homo sapiens]
631 gi 1209571529 NM_182527.2 calcium-binding protein 7  631 gi 1209571529 NM_182527.2 calcium-binding protein 7
[Homo sapiens]  [Homo sapiens]
632 gi 156090145 NM_001005920.2 jmjC domain-containing protein  632 gi 156090145 NM_001005920.2 jmjC domain-containing protein
8 [Homo sapiens]  8 [Homo sapiens]
633 gi 1166235894 NM_001114089.1 ectonucleoside triphosphate diphosphohydrolase 6 isoform 2 [Homo sapiens]  633 gi 1166235894 NM_001114089.1 ectonucleoside triphosphate diphosphohydrolase 6 isoform 2 [Homo sapiens]
634 gi 1189571686 NM_003731.2 Sjoegren Syndrome nuclear  634 gi 1189571686 NM_003731.2 Sjoegren Syndrome nuclear
autoantigen 1 [Homo sapiens] autoantigen 1 [Homo sapiens]
635 gi 1156071530 NM_145802.3 septin-6 isoform D [Homo 635 gi 1156071530 NM_145802.3 septin-6 isoform D [Homo
sapiens ]  sapiens]
636 gi 198961132 NM_025112.4 zinc finger protein ZXDC  636 gi 198961132 NM_025112.4 zinc finger protein ZXDC
isoform 1 [Homo sapiens] isoform 1 [Homo sapiens]
637 gi 166267729 NM_052844.3 WD repeat-containing protein 637 gi 166267729 NM_052844.3 WD repeat-containing protein
34 [Homo sapiens] 638 gi 1224586869 NM_138443.3 HAUS augmin-like complex 34 [Homo sapiens] 638 gi 1224586869 NM_138443.3 HOUSE augmin-like complex
subunit 1 [Homo sapiens] subunit 1 [Homo sapiens]
639 gi 1197276595 NM_006129.3 bone morphogenetic protein 1 isoform 3 precursor [Homo sapiens ] 639 gi 1197276595 NM_006129.3 bone morphogenetic protein 1 isoform 3 precursor [Homo sapiens]
640 gi 1161727457 AB370195.1 dihydropyrimidinase-like 2  640 gi 1161727457 AB370195.1 dihydropyrimidinase-like 2
long form [Homo sapiens] long form [Homo sapiens]
641 gi 189276761 NM_032940.2 DNA-directed RNA Polymerase II subunit RPB3 [Homo sapiens]641 gi 189276761 NM_032940.2 DNA-directed RNA polymerase II subunit RPB3 [Homo sapiens]
642 gi 1197209876 NM_003496.2 transformation/transcription domain-associated protein 642 gi 1197209876 NM_003496.2 transformation / transcription domain-associated protein
[Homo sapiens]  [Homo sapiens]
643 gi 1119393884 NM_005146.4 U4/U6.U5 tri-snRNP-associated protein 1 [Homo sapiens] 643 gi 1119393884 NM_005146.4 U4 / U6.U5 tri-snRNP-associated protein 1 [Homo sapiens]
644 gi 138201691 NM_007368.2 ras GTPase-activating protein 644 gi 138201691 NM_007368.2 ras GTPase-activating protein
3 [Homo sapiens]  3 [Homo sapiens]
645 gi 122091458 NM_014303.2 pescadillo homolog [Homo  645 gi 122091458 NM_014303.2 pescadillo homolog [Homo
sapiens ]  sapiens]
646 gi 155774983 NM_015660.2 GTPase IMAP family member 2  646 gi 155774983 NM_015660.2 GTPase IMAP family member 2
[Homo sapiens]  [Homo sapiens]
647 gi 1118498363 NM_001079520.1 dapper homolog 1 isoform 2  647 gi 1118498363 NM_001079520.1 dapper homolog 1 isoform 2
[Homo sapiens]  [Homo sapiens]
648 gi 185062625 NM_032377.3 transcription elongation  648 gi 185062625 NM_032377.3 transcription elongation
factor 1 homolog [Homo  factor 1 homolog [Homo
sapiens ]  sapiens]
649 gi 120357526 NM_002074.2 guanine nucleotide-binding  649 gi 120357526 NM_002074.2 guanine nucleotide-binding
protein G ( I ) /G ( S ) /G ( T ) subunit beta-1 [Homo sapiens]  protein G (I) / G (S) / G (T) subunit beta-1 [Homo sapiens]
650 gi 1194363754 NM_000852.3 glutathione S-transferase P  650 gi 1194363754 NM_000852.3 glutathione S-transferase P
[Homo sapiens]  [Homo sapiens]
651 gi 146255046 NM_001535.2 protein arginine N- methyltransferase 2 isoform 1 651 gi 146255046 NM_001535.2 protein arginine N- methyltransferase 2 isoform 1
[Homo sapiens]  [Homo sapiens]
652 gi 1157412269 NM_031203.2 heterogeneous nuclear  652 gi 1157412269 NM_031203.2 heterogeneous nuclear
ribonucleoprotein M isoform b [Homo sapiens]  ribonucleoprotein M isoform b [Homo sapiens]
653 gi 1223029468 NM_006159.2 protein kinase C-binding  653 gi 1223029468 NM_006159.2 protein kinase C-binding
protein NELL2 isoform b precursor [Homo sapiens]  protein NELL2 isoform b precursor [Homo sapiens]
654 gi 157863258 NM_001008897.1 T-complex protein 1 subunit alpha isoform b [Homo sapiens] 654 gi 157863258 NM_001008897.1 T-complex protein 1 subunit alpha isoform b [Homo sapiens]
655 gi 147078256 NM_003778.3 beta-1, 4-galactosyltransferase 655 gi 147078256 NM_003778.3 beta-1, 4-galactosyltransferase
4 [Homo sapiens]  4 [Homo sapiens]
656 gi 1145611425 NM_006814.3 proteasome inhibitor PI31  656 gi 1145611425 NM_006814.3 proteasome inhibitor PI31
subunit [Homo sapiens]  subunit [Homo sapiens]
657 gi 141406095 NM_014003.3 pre-mRNA-splicing factor ATP- dependent RNA helicase PRP16 [Homo sapiens]  657 gi 141406095 NM_014003.3 pre-mRNA splicing factor ATP-dependent RNA helicase PRP16 [Homo sapiens]
658 gi 1178557737 NM_006371.4 cartilage-associated protein precursor [Homo sapiens]  658 gi 1178557737 NM_006371.4 cartilage-associated protein precursor [Homo sapiens]
659 gi 191208424 NM_012469.3 pre-mRNA-processing factor 6  659 gi 191208424 NM_012469.3 pre-mRNA-processing factor 6
[Homo sapiens]  [Homo sapiens]
660 gi 151871119 NM_138401.2 multivesicular body subunit  660 gi 151871119 NM_138401.2 multivesicular body subunit
12A [Homo sapiens]  12A [Homo sapiens]
661 gi 1260898772 NM_176812.4 charged multivesicular body protein 4b [Homo sapiens] 661 gi 1260898772 NM_176812.4 charged multivesicular body protein 4b [Homo sapiens]
662 gi 1142388930 NM_152732.3 radial spoke head protein 9 homolog isoform 1 [Homo sapiens ] 662 gi 1142388930 NM_152732.3 radial spoke head protein 9 homologous isoform 1 [Homo sapiens]
663 gi 1320089575 NM_001004333.4 ribonuclease kappa [Homo  663 gi 1320089575 NM_001004333.4 ribonuclease kappa [Homo
sapiens ]  sapiens]
664 gi 176496473 NM_000018.2 very long-chain specific acyl- CoA dehydrogenase, 664 gi 176496473 NM_000018.2 very long-chain specific acyl CoA dehydrogenase,
mitochondrial isoform 1 precursor [Homo sapiens] mitochondrial isoform 1 precursor [Homo sapiens]
665 gi 121618333 NM_004003.2 carnitine acetyltransferase isoform 2 [Homo sapiens]665 gi 121618333 NM_004003.2 carnitine acetyltransferase isoform 2 [Homo sapiens]
666 gi 138201713 NM_001419.2 ELAV-like protein 1 [Homo 666 gi 138201713 NM_001419.2 ELAV-like protein 1 [Homo
sapiens ]  sapiens]
667 gi 1296531407 NM_198155.3 ESI protein homolog,  667 gi 1296531407 NM_198155.3 ESI protein homologue,
mitochondrial isoform Ib precursor [Homo sapiens] mitochondrial isoform Ib precursor [Homo sapiens]
668 gi 145269143 NM_012289.3 kelch-like ECH-associated 668 gi 145269143 NM_012289.3 kelch-like ECH-associated
protein 1 [Homo sapiens] protein 1 [Homo sapiens]
669 gi 141872645 NM_014780.3 cullin-7 isoform 2 [Homo 669 gi 141872645 NM_014780.3 cullin-7 isoform 2 [Homo
sapiens ]  sapiens]
670 gi 142544178 NM_012127.2 cipl-interacting zinc finger protein isoform 1 [Homo sapiens ]  670 gi 142544178 NM_012127.2 cipl-interacting zinc finger protein isoform 1 [Homo sapiens]
671 gi 134147607 NM_015953.3 nitric oxide synthase- interacting protein [Homo sapiens ]  671 gi 134147607 NM_015953.3 nitric oxide synthase-interacting protein [Homo sapiens]
672 gi 1124256477 NM_017974.3 autophagy-related protein 16-1 isoform 2 [Homo sapiens] 672 gi 1124256477 NM_017974.3 autophagy-related protein 16-1 isoform 2 [Homo sapiens]
673 gi 1110349768 NM_024296.3 coiled-coil domain-containing protein 28B [Homo sapiens]673 gi 1110349768 NM_024296.3 coiled-coil domain-containing protein 28B [Homo sapiens]
674 gi 140555764 BC064481.1 RNF187 protein [Homo sapiens]674 gi 140555764 BC064481.1 RNF187 protein [Homo sapiens]
675 gi 1194385887 AK304513.1 unnamed protein product [Homo sapiens ] 675 gi 1194385887 AK304513.1 unnamed protein product [Homo sapiens]
676 gi 1194328721 NM_001045556.2 src-like-adapter isoform a  676 gi 1194328721 NM_001045556.2 src-like adapter isoform a
[Homo sapiens]  [Homo sapiens]
677 gi 131652219 NM_133640.3 mediator of RNA Polymerase II transcription subunit 22 isoform b [Homo sapiens] 677 gi 131652219 NM_133640.3 mediator of RNA polymerase II transcription subunit 22 isoform b [Homo sapiens]
678 gi 1221136767 NM_000371.3 transthyretin precursor [Homo sapiens ]  678 gi 1221136767 NM_000371.3 transthyretin precursor [Homo sapiens]
679 gi 136287059 NM_182709.1 histone acetyltransferase KAT5 isoform 3 [Homo sapiens]  679 gi 136287059 NM_182709.1 histone acetyltransferase KAT5 isoform 3 [Homo sapiens]
680 gi 1261399873 NM_001009570.2 T-complex protein 1 subunit eta isoform b [Homo sapiens] 680 gi 1261399873 NM_001009570.2 T-complex protein 1 subunit eta isoform b [Homo sapiens]
681 gi 142544141 NM_202494.1 PDZ domain-containing protein 681 gi 142544141 NM_202494.1 PDZ domain-containing protein
GIPC1 isoform 2 [Homo sapiens] GIPC1 isoform 2 [Homo sapiens]
682 gi 188501739 NM_007032.5 TRIO and F-actin-binding 682 gi 188501739 NM_007032.5 TRIO and F-actin-binding
protein isoform 1 [Homo sapiens ]  protein isoform 1 [Homo sapiens]
683 gi 1144953896 NM_007184.3 nischarin [Homo sapiens]  683 gi 1144953896 NM_007184.3 nischarin [Homo sapiens]
684 gi 158331180 NM_134265.2 WD repeat and SOCS box- containing protein 1 isoform 2 [Homo sapiens]  684 gi 158331180 NM_134265.2 WD repeat and SOCS box containing protein 1 isoform 2 [Homo sapiens]
685 gi 1217272837 NM_006623.3 D-3-phosphoglycerate  685 g 1217272837 NM_006623.3 D-3-phosphoglycerate
dehydrogenase [Homo sapiens] dehydrogenase [Homo sapiens]
686 gi 1221136945 NM_014502.4 pre-mRNA-processing factor 19 686 gi 1221136945 NM_014502.4 pre-mRNA-processing factor 19
[Homo sapiens]  [Homo sapiens]
687 gi 1117553614 NM_016045.2 protein slowmo homolog 2 [Homo sapiens ]  687 gi 1117553614 NM_016045.2 protein slowmo homolog 2 [Homo sapiens]
688 gi 115967154 NM_016558.2 SCAN domain-containing protein  688 gi 115967154 NM_016558.2 SCAN domain-containing protein
1 isoform 1 [Homo sapiens] 1 isoform 1 [Homo sapiens]
689 gi 174048433 NM_016309.2 leucine carboxyl 689 gi 174048433 NM_016309.2 leucine carboxyl
methyltransferase 1 isoform a [Homo sapiens]  methyltransferase 1 isoform a [Homo sapiens]
690 gi 18922734 NM_018255.1 elongator complex protein 2 isoform 2 [Homo sapiens]  690 gi 18922734 NM_018255.1 elongator complex protein 2 isoform 2 [Homo sapiens]
691 gi 1145275199 NM_025080.3 L-asparaginase [Homo sapiens] 691 gi 1145275199 NM_025080.3 L-asparaginase [Homo sapiens]
692 gi 142734378 NM_138350.2 THAP domain-containing protein 3 isoform 2 [Homo sapiens]692 gi 142734378 NM_138350.2 THAP domain-containing protein 3 isoform 2 [Homo sapiens]
693 gi 1209915551 NM_001760.3 Gl/S-specific cyclin-D3 693 gi 1209915551 NM_001760.3 Gl / S-specific cyclin D3
isoform 2 [Homo sapiens] isoform 2 [Homo sapiens]
694 gi 1156071497 NM_004952.4 ephrin-A3 precursor [Homo 694 gi 1156071497 NM_004952.4 ephrin-A3 precursor [Homo
sapiens ]  sapiens]
695 gi 1225579056 NM_003049.3 sodium/bile acid cotransporter  695 gi 1225579056 NM_003049.3 sodium / bile acid cotransporter
[Homo sapiens]  [Homo sapiens]
696 gi 1284005308 NM_004260.3 ATP-dependent DNA helicase Q4  696 g 1284005308 NM_004260.3 ATP-dependent DNA helicase Q4
[Homo sapiens]  [Homo sapiens]
697 gi 150726974 NM_138501.4 trans-2 , 3-enoyl-CoA reductase  697 g1 150726974 NM_138501.4 trans-2,3-enoyl-CoA reductase
[Homo sapiens]  [Homo sapiens]
698 gi 159710114 NM_014679.3 centrosomal protein of 57 kDa  698 gi 159710114 NM_014679.3 centrosomal protein of 57 kDa
[Homo sapiens]  [Homo sapiens]
699 gi 145643118 NM_006117.2 enoyl-CoA delta isomerase 2, mitochondrial isoform 1 [Homo sapiens ]  699 gi 145643118 NM_006117.2 enoyl-CoA delta isomerase 2, mitochondrial isoform 1 [Homo sapiens]
700 gi 1111120323 NM_006621.4 putative  700 gi 1111120323 NM_006621.4 putative
adenosylhomocysteinase 2 isoform a [Homo sapiens] adenosylhomocysteinase 2 isoform a [Homo sapiens]
701 gi 133469977 NM_182835.1 secl family domain-containing protein 1 isoform b [Homo sapiens ] 701 gi 133469977 NM_182835.1 secl family domain-containing protein 1 isoform b [Homo sapiens]
702 gi 1118200355 NM_014394.2 growth hormone-inducible  702 gi 1118200355 NM_014394.2 growth hormone-inducible
transmembrane protein [Homo sapiens ]  transmembrane protein [Homo sapiens]
703 gi 159850648 NM_018443.2 zinc finger protein 302 [Homo sapiens ]  703 gi 159850648 NM_018443.2 zinc finger protein 302 [Homo sapiens]
704 gi 1142371393 NM_181505.2 protein Phosphatase 1  704 gi 1142371393 NM_181505.2 protein phosphatase 1
regulatory subunit 1B isoform 2 [Homo sapiens]  regulatory subunit 1B isoform 2 [Homo sapiens]
705 gi 1168480109 NM_005225.2 transcription factor E2F1 [Homo sapiens] 705 gi 1168480109 NM_005225.2 transcription factor E2F1 [Homo sapiens]
706 gi 151102290 NM_005395.2 postmeiotic segregation  706 gi 151102290 NM_005395.2 postmeiotic segregation
increased 2-like 3 isoform 1 [Homo sapiens]  increased 2-like 3 isoform 1 [Homo sapiens]
707 gi 148255969 NM_002969.3 mitogen-activated protein  707 gi 148255969 NM_002969.3 mitogen-activated protein
kinase 12 [Homo sapiens]  kinase 12 [Homo sapiens]
708 gi 1170650722 NM_014236.3 dihydroxyacetone phosphate  708 gi 1170650722 NM_014236.3 dihydroxyacetone phosphate
acyltransferase [Homo sapiens] acyltransferase [Homo sapiens]
709 gi 148527950 NM_013365.3 ADP-ribosylation factor- binding protein GGA1 isoform 1 [Homo sapiens] 709 gi 148527950 NM_013365.3 ADP-ribosylation factor-binding protein GGA1 isoform 1 [Homo sapiens]
710 gi 1213385322 NM_001137559.1 anaphase-promoting complex  710 gi 1213385322 NM_001137559.1 anaphase-promoting complex
subunit 5 isoform b [Homo sapiens ]  subunit 5 isoform b [Homo sapiens]
711 gi 1118498335 NM_016520.2 chromosome 9 open reading  711 gi 1118498335 NM_016520.2 chromosomes 9 open reading
frame 78 [Homo sapiens]  frame 78 [Homo sapiens]
712 gi 137537686 NM_018337.2 zinc finger protein 444 [Homo sapiens ]  712 gi 137537686 NM_018337.2 zinc finger protein 444 [Homo sapiens]
713 gi 168533248 NM_018476.3 protein BEX1 [Homo sapiens] 713 gi 168533248 NM_018476.3 protein BEX1 [Homo sapiens]
714 gi 1192449448 NM_022066.3 ubiquitin-con ugating enzyme 714 gi 1192449448 NM_022066.3 ubiquitin-conjugating enzyme
E2 0 [Homo sapiens]  E2 0 [Homo sapiens]
715 gi 112232384 NM_022730.1 COP9 signalosome complex  715 gi 112232384 NM_022730.1 COP9 signalosome complex
subunit 7b [Homo sapiens] subunit 7b [Homo sapiens]
716 gi 1201025398 NM_024334.2 transmembrane protein 43 [Homo sapiens ] 716 g1 1201025398 NM_024334.2 transmembrane protein 43 [Homo sapiens]
717 gi 138016923 NM_006253.4 5 ' -AMP-activated protein  717 gi 138016923 NM_006253.4 5'-AMP-activated protein
kinase subunit beta-1 [Homo sapiens ]  kinase subunit beta-1 [Homo sapiens]
718 gi 177404354 NM_003908.3 eukaryotic translation  718 gi 177404354 NM_003908.3 eukaryotic translation
initiation factor 2 subunit 2 [Homo sapiens] 719 gi 1237649014 NM_006824.2 probable rRNA-processing initiation factor 2 subunit 2 [Homo sapiens] 719 gi 1237649014 NM_006824.2 probable rRNA processing
protein EBP2 isoform 2 [Homo sapiens ]  protein EBP2 isoform 2 [Homo sapiens]
720 gi 140068460 NM_007284.3 twinfilin-2 [Homo sapiens] 720 gi 140068460 NM_007284.3 twinfilin-2 [Homo sapiens]
721 gi 139780570 NM_018116.2 protein misato homolog 1 [Homo sapiens ] 721 gi 139780570 NM_018116.2 protein misato homolog 1 [Homo sapiens]
722 gi 140068484 NM_022834.3 von Willebrand factor A  722 gi 140068484 NM_022834.3 from Willebrand factor A
domain-containing protein 1 isoform 1 precursor [Homo sapiens ]  domain-containing protein 1 isoform 1 precursor [Homo sapiens]
723 gi 1217416378 NM_001142650.1 heterogeneous nuclear  723 gi 1217416378 NM_001142650.1 heterogeneous nuclear
ribonucleoprotein L-like isoform 2 [Homo sapiens] ribonucleoprotein L-like isoform 2 [Homo sapiens]
724 gi 171834871 NM_178865.3 serine incorporator 2 isoform 724 gi 171834871 NM_178865.3 serine incorporator 2 isoform
1 [Homo sapiens]  1 [Homo sapiens]
725 gi 1258547122 NM_001151.3 ADP/ATP translocase 1 [Homo sapiens ]  725 gi 1258547122 NM_001151.3 ADP / ATP translocase 1 [Homo sapiens]
726 gi 1260593722 NM_001983.3 DNA excision repair protein  726 gi 1260593722 NM_001983.3 DNA excision repair protein
ERCC-1 isoform 2 [Homo  ERCC-1 isoform 2 [Homo
sapiens ]  sapiens]
727 gi 152630340 NM_002107.3 histone H3.3 [Homo sapiens] 727 gi 152630340 NM_002107.3 histone H3.3 [Homo sapiens]
728 gi 1219879807 NM_006325.3 GTP-binding nuclear protein 728 gi 1219879807 NM_006325.3 GTP-binding nuclear protein
Ran [Homo sapiens]  Ran [Homo sapiens]
729 gi 123111017 NM_152856.1 RNA-binding protein 10 isoform  729 gi 123111017 NM_152856.1 RNA-binding protein 10 isoform
2 [Homo sapiens]  2 [Homo sapiens]
730 gi 1157785644 NM_005876.4 striated muscle preferentially expressed protein kinase isoform 1 [Homo sapiens] 730 gi 1157785644 NM_005876.4 striated muscle preferentially expressed protein kinase isoform 1 [Homo sapiens]
731 gi 152851442 NM_006360.3 eukaryotic translation 731 gi 152851442 NM_006360.3 eukaryotic translation
initiation factor 3 subunit M [Homo sapiens] 732 gi 1197100772 NM_020320.3 probable arginyl-tRNA initiation factor 3 subunit M [Homo sapiens] 732 gi 1197100772 NM_020320.3 probable arginyl tRNA
synthetase, mitochondrial precursor [Homo sapiens] synthetase, mitochondrial precursor [Homo sapiens]
733 gi 189337269 NM_022749.5 retinoic acid induced 16 [Homo sapiens ] 733 gi 189337269 NM_022749.5 retinoic acid induced 16 [Homo sapiens]
734 gi 147174858 NM_025058.3 tripartite motif-containing protein 46 [Homo sapiens] 734 gi 147174858 NM_025058.3 tripartite motif-containing protein 46 [Homo sapiens]
735 gi 1109638742 NM_031478.4 hypothetical protein LOC83723 735 gi 1109638742 NM_031478.4 hypothetical protein LOC83723
[Homo sapiens]  [Homo sapiens]
736 gi 153729358 NM_138361.3 E3 ubiquitin-protein ligase  736 gi 153729358 NM_138361.3 E3 ubiquitin protein ligase
LRSAM1 isoform 1 [Homo  LRSAM1 isoform 1 [Homo
sapiens ]  sapiens]
737 gi 14506026 NM_002720.1 serine/threonine-protein  737 gi 14506026 NM_002720.1 serine / threonine protein
Phosphatase 4 catalytic subunit [Homo sapiens]  Phosphatase 4 catalytic subunit [Homo sapiens]
738 gi 173858576 NM_003254.2 metalloproteinase inhibitor 1 precursor [Homo sapiens] 738 gi 173858576 NM_003254.2 metalloproteinase inhibitor 1 precursor [Homo sapiens]
739 gi 1109150415 NM_012293.1 peroxidasin homolog precursor 739 gi 1109150415 NM_012293.1 peroxidase homolog precursor
[Homo sapiens]  [Homo sapiens]
740 gi 134365370 BX641004.1 hypothetical protein [Homo sapiens ]  740 gi 134365370 BX641004.1 hypothetical protein [Homo sapiens]
741 gi 16005793 NM_007213.1 PRA1 family protein 2 [Homo sapiens ]  741 gi 16005793 NM_007213.1 PRA1 family protein 2 [Homo sapiens]
742 gi 133859677 NM_017879.1 zinc finger protein 416 [Homo sapiens ]  742 gi 133859677 NM_017879.1 zinc finger protein 416 [Homo sapiens]
743 gi 1149274652 NM_020780.1 patched domain-containing  743 gi 1149274652 NM_020780.1 patched domain-containing
protein 2 [Homo sapiens] protein 2 [Homo sapiens]
744 gi 150511940 NM_133455.2 EMI domain-containing protein 744 gi 150511940 NM_133455.2 EMI domain-containing protein
1 [Homo sapiens]  1 [Homo sapiens]
745 gi 1187608297 NM_001660.3 ADP-ribosylation factor 4  745 gi 1187608297 NM_001660.3 ADP-ribosylation factor 4
[Homo sapiens] 746 gi 134335193 NM_182720.1 cAMP-responsive element [Homo sapiens] 746 gi 134335193 NM_182720.1 cAMP-responsive element
modulator isoform g [Homo sapiens ]  modulator isoform g [Homo sapiens]
747 gi 140549399 NM_001894.4 casein kinase I isoform  747 gi 140549399 NM_001894.4 casein kinase I isoform
epsilon [Homo sapiens]  epsilon [Homo sapiens]
748 gi 1197245333 NM_005273.3 guanine nucleotide-binding  748 gi 1197245333 NM_005273.3 guanine nucleotide-binding
protein G ( I ) /G ( S ) /G ( T ) subunit beta-2 [Homo sapiens]  protein G (I) / G (S) / G (T) subunit beta-2 [Homo sapiens]
749 gi 1188497749 NM_033500.2 hexokinase-1 isoform HKI-td  749 gi 1188497749 NM_033500.2 hexokinase-1 isoform HKI-td
[Homo sapiens]  [Homo sapiens]
750 gi 1187828416 NM_005586.3 myoD family inhibitor [Homo sapiens ]  750 gi 1187828416 NM_005586.3 myoD family inhibitor [Homo sapiens]
751 gi 138679891 NM_006223.2 peptidyl-prolyl cis-trans  751 gi 138679891 NM_006223.2 peptidyl-prolyl cis-trans
isomerase NIMA-interacting 4 isoform 1 [Homo sapiens] isomerase NIMA interacting 4 isoform 1 [Homo sapiens]
752 gi 1221218992 NM_003475.3 ras association domain- containing protein 7 isoform 1 [Homo sapiens] 752 gi 1221218992 NM_003475.3 ras association domain-containing protein 7 isoform 1 [Homo sapiens]
753 gi 1156071485 NM_003680.3 tyrosyl-tRNA synthetase,  753 gi 1156071485 NM_003680.3 tyrosyl-tRNA synthetase,
cytoplasmic [Homo sapiens] cytoplasmic [Homo sapiens]
754 gi 158530880 NM_004675.2 GTP-binding protein Di-Ras3 754 gi 158530880 NM_004675.2 GTP-binding protein Di-Ras3
[Homo sapiens]  [Homo sapiens]
755 gi 1150170698 NM_015656.1 kinesin-like protein KIF26A  755 gi 1150170698 NM_015656.1 kinesin-like protein KIF26A
[Homo sapiens]  [Homo sapiens]
756 gi 1198386318 NM_016188.4 actin-like protein 6B [Homo sapiens ]  756 gi 1198386318 NM_016188.4 actin-like protein 6B [Homo sapiens]
757 gi 149574501 NM_016243.2 NADH-cytochrome b5 reductase 1  757 gi 149574501 NM_016243.2 NADH cytochrome b5 reductase 1
[Homo sapiens]  [Homo sapiens]
758 gi 134147350 NM_023940.2 ras-like protein family member  758 gi 134147350 NM_023940.2 ras-like protein family member
IIB [Homo sapiens]  IIB [Homo sapiens]
759 gi 155749599 NM_032451.1 protein spire homolog 2 [Homo sapiens ] 759 gi 155749599 NM_032451.1 protein spire homologue 2 [Homo sapiens]
760 gi 139992615 BC064477.1 PIM3 protein [Homo sapiens] 760 gi 139992615 BC064477.1 PIM3 protein [Homo sapiens]
761 gi 156118216 NM_001008216.1 UDP-glucose 4-epimerase [Homo sapiens ] 761 gi 156118216 NM_001008216.1 UDP-glucose 4-epimerase [Homo sapiens]
762 gi 127502382 NM_172316.1 homeobox protein Meis2 isoform h [Homo sapiens]  762 gi 127502382 NM_172316.1 homeobox protein Meis2 isoform h [Homo sapiens]
763 gi 191208422 NM_003302.2 thyroid receptor-interacting protein 6 [Homo sapiens] 763 gi 191208422 NM_003302.2 thyroid receptor-interacting protein 6 [Homo sapiens]
764 gi 1154800448 NM_003433.3 zinc finger protein 132 [Homo sapiens ] 764 gi 1154800448 NM_003433.3 zinc finger protein 132 [Homo sapiens]
765 gi 141872688 NM_003660.2 liprin-alpha-3 [Homo sapiens] 765 gi 141872688 NM_003660.2 liprin-alpha-3 [Homo sapiens]
766 gi 1197382802 NM_006769.3 LIM domain transcription 766 gi 1197382802 NM_006769.3 LIM domain transcription
factor LM04 [Homo sapiens] factor LM04 [Homo sapiens]
767 gi 1253735774 NM_001162383.1 rho guanine nucleotide 767 gi 1253735774 NM_001162383.1 rho guanine nucleotide
exchange factor 2 isoform 1 [Homo sapiens]  exchange factor 2 isoform 1 [Homo sapiens]
768 gi 15730026 NM_006559.1 KH domain-containing, RNA- binding, signal transduction- associated protein 1 [Homo sapiens ]  768 gi 15730026 NM_006559.1 KH domain-containing, RNA-binding, signal transduction-associated protein 1 [Homo sapiens]
769 gi 1219555664 NM_001143780.1 solute carrier family 25  769 gi 1219555664 NM_001143780.1 solute carrier family 25
member 39 isoform a [Homo sapiens ]  member 39 isoform a [Homo sapiens]
770 gi 141393557 NM_018032.3 putative RNA-binding protein  770 gi 141393557 NM_018032.3 putative RNA-binding protein
Luc7-like 1 isoform a [Homo sapiens ]  Luc7-like 1 isoform a [Homo sapiens]
771 gi 1149274623 NM_030915.3 protein LBH [Homo sapiens] 771 gi 1149274623 NM_030915.3 protein LBH [Homo sapiens]
772 gi 158761547 NM_032538.1 tau-tubulin kinase 1 [Homo sapiens ] 772 gi 158761547 NM_032538.1 tau-tubulin kinase 1 [Homo sapiens]
773 gi 134147461 NM_033414.2 zinc finger protein 622 [Homo sapiens ] 774 gi 1304555613 NM_152743.3 BRCAl-associated ATM activator 773 gi 134147461 NM_033414.2 zinc finger protein 622 [Homo sapiens] 774 gi 1304555613 NM_152743.3 BRCAl-associated ATM activator
1 [Homo sapiens]  1 [Homo sapiens]
775 gi 1229608893 NM_181723.2 EF-hand domain-containing  775 gi 1229608893 NM_181723.2 EF-hand domain-containing
family member A2 [Homo  family member A2 [Homo
sapiens ]  sapiens]
776 gi 1119964727 NM_152783.3 D-2-hydroxyglutarate  776 gi 1119964727 NM_152783.3 D-2-hydroxyglutarates
dehydrogenase, mitochondrial precursor [Homo sapiens] dehydrogenase, mitochondrial precursor [Homo sapiens]
777 gi 1109148541 NM_001605.2 alanyl-tRNA synthetase, 777 gi 1109148541 NM_001605.2 alanyl-tRNA synthetase,
cytoplasmic [Homo sapiens] cytoplasmic [Homo sapiens]
778 gi 183700234 NM_001967.3 eukaryotic initiation factor 778 gi 183700234 NM_001967.3 eukaryotic initiation factor
4A-II [Homo sapiens]  4A-II [Homo sapiens]
779 gi 1105990523 NM_000182.4 trifunctional enzyme subunit alpha, mitochondrial precursor [Homo sapiens]  779 gi 1105990523 NM_000182.4 trifunctional enzyme subunit alpha, mitochondrial precursor [Homo sapiens]
780 gi 118201902 NM_002109.3 histidyl-tRNA synthetase,  780 gi 118201902 NM_002109.3 histidyl-tRNA synthetase,
cytoplasmic [Homo sapiens] cytoplasmic [Homo sapiens]
781 gi 178190460 NM_000984.5 60S ribosomal protein L23a 781 gi 178190460 NM_000984.5 60S ribosomal protein L23a
[Homo sapiens]  [Homo sapiens]
782 gi 178190459 NM_000978.3 60S ribosomal protein L23  782 gi 178190459 NM_000978.3 60S ribosomal protein L23
[Homo sapiens]  [Homo sapiens]
783 gi 145446742 NM_007372.2 ATP-dependent RNA helicase  783 gi 145446742 NM_007372.2 ATP-dependent RNA helicase
DDX42 [Homo sapiens]  DDX42 [Homo sapiens]
784 gi 161102726 NM_015315.3 la-related protein 1 isoform 1  784 g1 161102726 NM_015315.3 la-related protein 1 isoform 1
[Homo sapiens]  [Homo sapiens]
785 gi 1112382376 NM_014501.2 ubiquitin-con ugating enzyme  785 gi 1112382376 NM_014501.2 ubiquitin-conjugating enzyme
E2 S [Homo sapiens]  E2 S [Homo sapiens]
786 gi 182830423 NM_001037533.1 GON-4-like protein isoform a  786 gi 182830423 NM_001037533.1 GON-4-like protein isoform a
[Homo sapiens]  [Homo sapiens]
787 gi 1110227844 NM_024112.3 hypothetical protein LOC79095  787 gi 1110227844 NM_024112.3 hypothetical protein LOC79095
[Homo sapiens] 788 gi 1149363677 NM_199287.2 coiled-coil domain-containing protein 137 [Homo sapiens][Homo sapiens] 788 gi 1149363677 NM_199287.2 coiled-coil domain-containing protein 137 [Homo sapiens]
789 gi 1194353969 NM_000681.3 alpha-2A adrenergic receptor 789 gi 1194353969 NM_000681.3 alpha-2A adrenergic receptor
[Homo sapiens]  [Homo sapiens]
790 gi 111038670 NM_004339.2 pituitary tumor-transforming gene 1 protein-interacting protein precursor [Homo sapiens ]  790 gi 111038670 NM_004339.2 pituitary tumor-transforming gene 1 protein-interacting protein precursor [Homo sapiens]
791 gi 187159810 NM_004357.4 CD151 antigen [Homo sapiens] 791 gi 187159810 NM_004357.4 CD151 antigen [Homo sapiens]
792 gi 1166235161 NM_001839.3 calponin-3 [Homo sapiens]792 gi 1166235161 NM_001839.3 calponin-3 [Homo sapiens]
793 gi 146411186 NM_005234.3 nuclear receptor subfamily 2 group F member 6 [Homo 793 gi 146411186 NM_005234.3 nuclear receptor subfamily 2 group F member 6 [Homo
sapiens ]  sapiens]
794 gi 1156071503 NM_006908.4 ras-related C3 botulinum toxin  794 gi 1156071503 NM_006908.4 ras-related C3 botulinum toxin
Substrate 1 isoform Racl [Homo sapiens ]  Substrates 1 isoform Racl [Homo sapiens]
795 gi 137577134 NM_003348.3 ubiquitin-con ugating enzyme  795 gi 137577134 NM_003348.3 ubiquitin-con ugating enzyme
E2 N [Homo sapiens]  E2 N [Homo sapiens]
796 gi 137594440 NM_003437.2 zinc finger protein 136 [Homo sapiens ]  796 gi 137594440 NM_003437.2 zinc finger protein 136 [Homo sapiens]
797 gi 1197333754 NM_006764.4 interferon-related  797 gi 1197333754 NM_006764.4 interferon-related
developmental regulator 2  developmental regulator 2
[Homo sapiens]  [Homo sapiens]
798 gi 131652256 NM_005461.3 transcription factor MafB  798 gi 131652256 NM_005461.3 transcription factor MafB
[Homo sapiens]  [Homo sapiens]
799 gi 1114796625 NM_013356.2 monocarboxylate transporter 3  799 gi 1114796625 NM_013356.2 monocarboxylate transporter 3
[Homo sapiens]  [Homo sapiens]
800 gi 118496982 NM_015526.1 CAP-Gly domain-containing  800 gi 118496982 NM_015526.1 CAP-Gly domain-containing
linker protein 3 [Homo  left protein 3 [Homo
sapiens ]  sapiens]
801 gi 1323635445 NM_020394.4 zinc finger protein 695 isoform 1 [Homo sapiens]801 gi 1323635445 NM_020394.4 zinc finger protein 695 isoform 1 [Homo sapiens]
802 gi 1197245455 NM_022574.4 PERQ amino acid-rich with GYF domain-containing protein 1 [Homo sapiens] 802 gi 1197245455 NM_022574.4 PERQ amino acid-rich with GYF domain-containing protein 1 [Homo sapiens]
803 gi 1186928846 NM_032830.2 cirhin [Homo sapiens]  803 gi 1186928846 NM_032830.2 cirhin [Homo sapiens]
804 gi 162241010 NM_005163.2 RAC-alpha serine/threonine- protein kinase [Homo sapiens] 804 gi 162241010 NM_005163.2 RAC-alpha serine / threonine protein kinase [Homo sapiens]
805 gi 138372939 NM_001185.2 zinc-alpha-2-glycoprotein 805 gi 138372939 NM_001185.2 zinc alpha-2-glycoprotein
precursor [Homo sapiens] precursor [Homo sapiens]
806 gi 121735620 NM_005918.2 malate dehydrogenase, 806 gi 121735620 NM_005918.2 malate dehydrogenase,
mitochondrial precursor [Homo sapiens ]  mitochondrial precursor [Homo sapiens]
807 gi 1115387093 NM_003000.2 succinate dehydrogenase  807 gi 1115387093 NM_003000.2 succinate dehydrogenase
[ubiquinone] iron-sulfur subunit, mitochondrial precursor [Homo sapiens] [ubiquinone] iron-sulfur subunit, mitochondrial precursor [Homo sapiens]
808 gi 154607088 NM_001005914.1 semaphorin-3B isoform 2 808 gi 154607088 NM_001005914.1 semaphorin-3B isoform 2
precursor [Homo sapiens] precursor [Homo sapiens]
809 gi 156550050 NM_006590.2 U4/U6.U5 tri-snRNP-associated protein 2 [Homo sapiens]809 gi 156550050 NM_006590.2 U4 / U6.U5 tri-snRNP-associated protein 2 [Homo sapiens]
810 gi 138027945 NM_006833.4 COP9 signalosome complex 810 gi 138027945 NM_006833.4 COP9 signalosome complex
subunit 6 [Homo sapiens] subunit 6 [Homo sapiens]
811 gi 157617038 NM_015140.2 tubulin—tyrosine ligase-like protein 12 [Homo sapiens]811 gi 157617038 NM_015140.2 tubulin-tyrosine ligase-like protein 12 [Homo sapiens]
812 gi 1110227859 NM_016305.2 SS18-like protein 2 [Homo 812 gi 1110227859 NM_016305.2 SS18-like protein 2 [Homo
sapiens ]  sapiens]
813 gi 1222831567 NM_033082.3 SAP domain-containing  813 gi 1222831567 NM_033082.3 SAP domain-containing
ribonucleoprotein [Homo sapiens ]  ribonucleoprotein [Homo sapiens]
814 gi 140548381 NM_199249.1 multidrug resistance-related protein [Homo sapiens] 815 gi 189886471 NM_206538.2 hematopoietic signal peptide- containing isoform 2 [Homo sapiens ] 814 gi 140548381 NM_199249.1 multidrug resistance-related protein [Homo sapiens] 815 gi 189886471 NM_206538.2 hematopoietic signal peptide containing isoform 2 [Homo sapiens]
816 gi 119913440 NM_002149.2 hippocalcin-like protein 1  816 gi 119913440 NM_002149.2 hippocalcin-like protein 1
[Homo sapiens]  [Homo sapiens]
817 gi 1316983123 NM_021029.5 60S ribosomal protein L36a isoform a [Homo sapiens] 817 gi 1316983123 NM_021029.5 60S ribosomal protein L36a isoform a [Homo sapiens]
818 gi 155925657 NM_002997.4 syndecan-1 precursor [Homo sapiens ] 818 gi 155925657 NM_002997.4 syndecan-1 precursor [Homo sapiens]
819 gi 146877103 NM_003367.2 upstream stimulatory factor 2 isoform 1 [Homo sapiens] 819 gi 146877103 NM_003367.2 upstream stimulatory factor 2 isoform 1 [Homo sapiens]
820 gi 188853068 NM_000638.3 vitronectin precursor [Homo sapiens ] 820 gi 188853068 NM_000638.3 vitronectin precursor [Homo sapiens]
821 gi 14503824 NM_003505.1 frizzled-1 precursor [Homo sapiens ]  821 gi 14503824 NM_003505.1 frizzled-1 precursor [Homo sapiens]
822 gi 1133908634 NM_012109.2 transmembrane protein 59-like precursor [Homo sapiens] 822 gi 1133908634 NM_012109.2 transmembrane protein 59-like precursor [Homo sapiens]
823 gi 1151101234 NM_012461.2 TERFl-interacting nuclear 823 gi 1151101234 NM_012461.2 TERFl-interacting nuclear
factor 2 isoform 2 [Homo sapiens ]  factor 2 isoform 2 [Homo sapiens]
824 gi 1221316691 NM_020309.3 vesicular glutamate  824 gi 1221316691 NM_020309.3 vesicular glutamate
transporter 1 [Homo sapiens] transporter 1 [Homo sapiens]
825 gi 1165932369 NM_024582.4 protocadherin Fat 4 precursor 825 gi 1165932369 NM_024582.4 protocadherin Fat 4 precursor
[Homo sapiens]  [Homo sapiens]
826 gi 152353305 NM_001005210.1 leucine-rich repeat-containing protein 55 [Homo sapiens] 826 gi 152353305 NM_001005210.1 leucine-rich repeat-containing protein 55 [Homo sapiens]
827 gi 1194378373 AK294825.1 unnamed protein product [Homo sapiens ] 827 gi 1194378373 AK294825.1 unnamed protein product [Homo sapiens]
828 gi 132454740 NM_001235.2 serpin Hl precursor [Homo  828 gi 132454740 NM_001235.2 serpin Hl precursor [Homo
sapiens ]  sapiens]
829 gi 133598925 NM_005506.2 lysosome membrane protein 2 isoform 1 [Homo sapiens]829 gi 133598925 NM_005506.2 lysosome membrane protein 2 isoform 1 [Homo sapiens]
830 gi 118201904 NM_000175.2 glucose-6-phosphate isomerase isoform 2 [Homo sapiens]830 gi 118201904 NM_000175.2 glucose-6-phosphate isomerase isoform 2 [Homo sapiens]
831 gi 1161169039 NM_004548.2 NADH dehydrogenase 831 gi 1161169039 NM_004548.2 NADH dehydrogenase
[ubiquinone] 1 beta subcomplex subunit 10 [Homo sapiens] [ubiquinone] 1 beta subcomplex subunit 10 [Homo sapiens]
832 gi 1141801911 NM_003295.2 translationally-controlled 832 gi 1141801911 NM_003295.2 translationally-controlled
tumor protein [Homo sapiens] tumor protein [Homo sapiens]
833 gi 123397695 NM_152925.1 copine-1 isoform a [Homo 833 gi 123397695 NM_152925.1 copine-1 isoform a [Homo
sapiens ]  sapiens]
834 gi 1197313723 NM_005736.3 alpha-centractin [Homo  834 gi 1197313723 NM_005736.3 alpha-centractin [Homo
sapiens ]  sapiens]
835 gi 134147665 NM_006374.3 serine/threonine-protein  835 gi 134147665 NM_006374.3 serine / threonine protein
kinase 25 [Homo sapiens] kinase 25 [Homo sapiens]
836 gi 154112115 NM_006802.2 splicing factor 3A subunit 3 836 gi 154112115 NM_006802.2 splicing factor 3A subunit 3
[Homo sapiens]  [Homo sapiens]
837 gi 163082031 NM_015089.2 cullin-9 [Homo sapiens]  837 gi 163082031 NM_015089.2 cullin-9 [Homo sapiens]
838 gi 141872442 NM_199368.1 Short transient receptor  838 gi 141872442 NM_199368.1 Short transient receptor
Potential Channel 4-associated protein isoform b [Homo sapiens ]  Potential Channel 4-associated protein isoform b [Homo sapiens]
839 gi 1197100212 NM_001610.2 lysosomal acid Phosphatase isoform 1 precursor [Homo sapiens ]  839 gi 1197100212 NM_001610.2 lysosomal acid phosphatase isoform 1 precursor [Homo sapiens]
840 gi 1169636438 NM_000078.2 cholesteryl ester transfer protein precursor [Homo sapiens ]  840 gi 1169636438 NM_000078.2 cholesteryl ester transfer protein precursor [Homo sapiens]
841 gi 1169259765 NM_001514.5 transcription initiation  841 gi 1169259765 NM_001514.5 transcription initiation
factor IIB [Homo sapiens] factor IIB [Homo sapiens]
842 gi 163253297 NM_003132.2 spermidine synthase [Homo 842 gi 163253297 NM_003132.2 spermidine synthase [Homo
sapiens ] 843 gi 137577149 NM_016453.2 NCK-interacting protein with sapiens] 843 gi 137577149 NM_016453.2 NCK-interacting protein with
SH3 domain isoform 1 [Homo sapiens ]  SH3 domain isoform 1 [Homo sapiens]
844 gi 137622893 NM_194460.1 RING finger protein 126 [Homo sapiens ]  844 gi 137622893 NM_194460.1 RING finger protein 126 [Homo sapiens]
845 gi 129171685 NM_030768.2 integrin-linked kinase- associated serine/threonine Phosphatase 2C [Homo sapiens] 845 gi 129171685 NM_030768.2 integrin-linked kinase-associated serine / threonine phosphatase 2C [Homo sapiens]
846 gi 114150140 NM_032346.1 programmed cell death protein 846 gi 114150140 NM_032346.1 programmed cell death protein
2-like [Homo sapiens]  2-like [Homo sapiens]
847 gi 1119120876 NM_133474.2 zinc finger protein 721 [Homo sapiens ]  847 gi 1119120876 NM_133474.2 zinc finger protein 721 [Homo sapiens]
848 gi 1257471022 NM_004930.3 F-actin-capping protein  848 gi 1257471022 NM_004930.3 F-actin-capping protein
subunit beta isoform 1 [Homo sapiens ]  subunit beta isoform 1 [Homo sapiens]
849 gi 119718776 NM_004111.4 flap endonuclease 1 [Homo  849 gi 119718776 NM_004111.4 Flap endonuclease 1 [Homo
sapiens ]  sapiens]
850 gi 124797084 NM_002265.4 importin subunit beta-1 [Homo sapiens ]  850 gi 124797084 NM_002265.4 importin subunit beta-1 [Homo sapiens]
851 gi 1221316755 NM_000425.3 neural cell adhesion molecule  851 gi 1221316755 NM_000425.3 neuronal cell adhesion molecule
LI isoform 1 precursor [Homo sapiens ]  LI isoform 1 precursor [Homo sapiens]
852 gi 1171543862 NM_000289.4 6-phosphofructokinase, muscle type isoform 2 [Homo sapiens] 852 gi 1171543862 NM_000289.4 6-phosphofructokinase, muscle type isoform 2 [Homo sapiens]
853 gi 14505940 NM_000938.1 DNA-directed RNA Polymerase II subunit RPB2 [Homo sapiens]853 gi 14505940 NM_000938.1 DNA-directed RNA polymerase II subunit RPB2 [Homo sapiens]
854 gi 1156631004 NM_002812.4 26S proteasome non-ATPase 854 gi 1156631004 NM_002812.4 26S proteasome non-ATPase
regulatory subunit 8 [Homo sapiens ]  regulatory subunit 8 [Homo sapiens]
855 gi 151477705 NM_003078.3 SWI/SNF-related matrix- associated actin-dependent regulator of chromatin 855 gi 151477705 NM_003078.3 SWI / SNF-related matrix-associated actin-dependent regulator of chromatin
subfamily D member 3 isoform 1 [Homo sapiens]  subfamily D member 3 isoform 1 [Homo sapiens]
856 gi 138505154 NM_003195.4 transcription elongation  856 gi 138505154 NM_003195.4 transcription elongation
factor A protein 2 isoform a [Homo sapiens]  factor A protein 2 isoform a [Homo sapiens]
857 gi 163162571 NM_005998.3 T-complex protein 1 subunit gamma isoform a [Homo sapiens] 857 gi 163162571 NM_005998.3 T-complex protein 1 subunit gamma isoform a [Homo sapiens]
858 gi 155769586 NM_003703.1 nucleolar protein 14 [Homo 858 gi 155769586 NM_003703.1 nucleolar protein 14 [Homo
sapiens ]  sapiens]
859 gi 195147537 NM_006051.3 amyloid beta A4 precursor  859 gi 195147537 NM_006051.3 amyloid beta A4 precursor
protein-binding family B member 3 isoform d [Homo sapiens ]  protein-binding family B member 3 isoform d [Homo sapiens]
860 gi 18922332 NM_018049.1 pleckstrin homology domain- containing family J member 1 [Homo sapiens]  860 gi 18922332 NM_018049.1 pleckstrin homology domain- containing family J member 1 [Homo sapiens]
861 gi 132484989 NM_018639.3 WD repeat and SOCS box- containing protein 2 [Homo sapiens ]  861 gi 132484989 NM_018639.3 WD repeat and SOCS box-containing protein 2 [Homo sapiens]
862 gi 1215599267 NM_032039.2 protein ITFG3 [Homo sapiens] 862 gi 1215599267 NM_032039.2 protein ITFG3 [Homo sapiens]
863 gi 121362049 NM_032357.2 coiled-coil domain-containing protein 115 [Homo sapiens]863 gi 121362049 NM_032357.2 coiled-coil domain-containing protein 115 [Homo sapiens]
864 gi 1160420327 NM_194279.2 iron-sulfur Cluster assembly 2 homolog, mitochondrial 864 gi 1160420327 NM_194279.2 iron-sulfur cluster assembly 2 homologous, mitochondrial
precursor [Homo sapiens]  precursor [Homo sapiens]
865 gi 1111494227 NM_001418.3 eukaryotic translation  865 gi 1111494227 NM_001418.3 eukaryotic translation
initiation factor 4 gamma 2 isoform 1 [Homo sapiens]  initiation factor 4 gamma 2 isoform 1 [Homo sapiens]
866 gi 161835203 NM_001013436.1 3-mercaptopyruvate  866 gi 161835203 NM_001013436.1 3-mercaptopyruvate
sulfurtransferase isoform 2 [Homo sapiens] sulfur transferase isoform 2 [Homo sapiens]
867 gi 139725687 NM_005002.3 NADH dehydrogenase  867 gi 139725687 NM_005002.3 NADH dehydrogenase
[ubiquinone] 1 alpha  [ubiquinone] 1 alpha
subcomplex subunit 9,  subcomplex subunit 9,
mitochondrial precursor [Homo sapiens ]  mitochondrial precursor [Homo sapiens]
868 gi 1106049291 NM_022172.2 pyruvate carboxylase,  868 gi 1106049291 NM_022172.2 pyruvate carboxylase,
mitochondrial precursor [Homo sapiens ]  mitochondrial precursor [Homo sapiens]
869 gi 1156416002 NM_004168.2 succinate dehydrogenase  869 gi 1156416002 NM_004168.2 succinate dehydrogenase
[ubiquinone] flavoprotein subunit, mitochondrial precursor [Homo sapiens] [ubiquinone] flavoprotein subunit, mitochondrial precursor [Homo sapiens]
870 gi 1209413761 NM_017586.2 calcium Channel flower homolog isoform a [Homo sapiens]870 gi 1209413761 NM_017586.2 calcium Channel flower homologous isoform a [Homo sapiens]
871 gi 1166197689 NM_001114090.1 ephexin-1 isoform 2 [Homo 871 gi 1166197689 NM_001114090.1 ephexin-1 isoform 2 [Homo
sapiens ]  sapiens]
872 gi 175677342 NM_015544.2 transmembrane protein 98 [Homo sapiens ]  872 gi 175677342 NM_015544.2 transmembrane protein 98 [Homo sapiens]
873 gi 1187829451 NM_001127231.1 autism susceptibility gene 2 protein isoform 2 [Homo sapiens ]  873 gi 1187829451 NM_001127231.1 autism susceptibility gene 2 protein isoform 2 [Homo sapiens]
874 gi 1218751872 NM_018645.4 transcription cofactor HES-6 isoform a [Homo sapiens] 874 gi 1218751872 NM_018645.4 transcription cofactor HES-6 isoform a [Homo sapiens]
875 gi 191807118 NM_025141.3 TM2 domain-containing protein 875 g1 191807118 NM_025141.3 TM2 domain-containing protein
3 isoform b [Homo sapiens] 3 isoform b [Homo sapiens]
876 gi 1114520614 NM_001954.4 epithelial discoidin domain- containing receptor 1 isoform 1 precursor [Homo sapiens]876 gi 1114520614 NM_001954.4 epithelial discoidin domain containing receptor 1 isoform 1 precursor [Homo sapiens]
877 gi 1186659502 NM_031263.2 heterogeneous nuclear 877 gi 1186659502 NM_031263.2 heterogeneous nuclear
ribonucleoprotein K isoform a [Homo sapiens] ribonucleoprotein K isoform a [Homo sapiens]
878 gi 1313760623 NM_000442.4 platelet endothelial cell  878 gi 1313760623 NM_000442.4 platelet endothelial cell
adhesion molecule precursor [Homo sapiens]  adhesion molecule precursor [Homo sapiens]
879 gi 134335279 NM_002811.3 26S proteasome non-ATPase  879 gi 134335279 NM_002811.3 26S proteasome non-ATPase
regulatory subunit 7 [Homo sapiens ]  regulatory subunit 7 [Homo sapiens]
880 gi 130581139 NM_006263.2 proteasome activator complex subunit 1 isoform 1 [Homo sapiens ]  880 gi 130581139 NM_006263.2 proteasome activator complex subunit 1 isoform 1 [Homo sapiens]
881 gi 178191800 NM_000997.4 60S ribosomal protein L37  881 gi 178191800 NM_000997.4 60S ribosomal protein L37
[Homo sapiens]  [Homo sapiens]
882 gi 1197927095 NM_001030.4 40S ribosomal protein S27  882 gi 1197927095 NM_001030.4 40S ribosomal protein S27
[Homo sapiens]  [Homo sapiens]
883 gi 121396499 NM_003609.2 HIRA-interacting protein 3  883 gi 121396499 NM_003609.2 HIRA-interacting protein 3
[Homo sapiens]  [Homo sapiens]
884 gi 125777595 NM_003648.2 diacylglycerol kinase delta isoform 1 [Homo sapiens] 884 gi 125777595 NM_003648.2 diacylglycerol kinase delta isoform 1 [Homo sapiens]
885 gi 152486264 NM_006029.4 paraneoplastic antigen Mal 885 gi 152486264 NM_006029.4 paraneoplastic antigen mal
[Homo sapiens]  [Homo sapiens]
886 gi 157242773 NM_014680.2 hypothetical protein LOC9703 precursor [Homo sapiens] 886 gi 157242773 NM_014680.2 hypothetical protein LOC9703 precursor [Homo sapiens]
887 gi 1151108508 NM_014859.4 rho GTPase-activating protein 887 gi 1151108508 NM_014859.4 rho GTPase-activating protein
44 [Homo sapiens]  44 [Homo Sapiens]
888 gi 1104876422 NM_006040.2 heparan sulfate glucosamine 3- O-sulfotransferase 4 [Homo sapiens ]  888 gi 1104876422 NM_006040.2 heparan sulfate glucosamine 3- O-sulfotransferase 4 [Homo sapiens]
889 gi 1110349723 NM_021267.3 LAG1 longevity assurance  889 gi 1110349723 NM_021267.3 LAG1 longevity assurance
homolog 1 isoform 1 [Homo sapiens ]  homologue 1 isoform 1 [Homo sapiens]
890 gi 1166795249 NM_006845.3 kinesin-like protein KIF2C [Homo sapiens] 890 gi 1166795249 NM_006845.3 kinesin-like protein KIF2C [Homo sapiens]
891 gi 138570153 NM_012279.2 zinc finger protein 346 [Homo sapiens ]  891 gi 138570153 NM_012279.2 zinc finger protein 346 [Homo sapiens]
892 gi 1156602659 NM_018206.4 vacuolar protein sorting- associated protein 35 [Homo sapiens ]  892 gi 1156602659 NM_018206.4 vacuolar protein sorting-associated protein 35 [Homo sapiens]
893 gi 117978480 NM_080413.1 vacuolar protein sorting- associated protein 16 homolog isoform 3 [Homo sapiens] 893 gi 117978480 NM_080413.1 vacuolar protein sorting-associated protein 16 homologous isoform 3 [Homo sapiens]
894 gi 140807483 NM_030815.2 p53 and DNA damage-regulated protein 1 [Homo sapiens]894 gi 140807483 NM_030815.2 p53 and DNA damage-regulated protein 1 [Homo sapiens]
895 gi 147132623 NM_145798.2 oxysterol-binding protein- related protein 7 [Homo sapiens ] 895 gi 147132623 NM_145798.2 oxysterol-binding protein-related protein 7 [Homo sapiens]
896 gi 186198309 NM_001039355.1 mitochondrial  896 gi 186198309 NM_001039355.1 mitochondrial
carnitine/acylcarnitine carrier protein CACL [Homo sapiens ]  carnitine / acylcarnitine carrier protein CACL [Homo sapiens]
897 gi 1194097322 NM_004092.3 enoyl-CoA hydratase,  897 gi 1194097322 NM_004092.3 enoyl-CoA hydratase,
mitochondrial precursor [Homo sapiens ]  mitochondrial precursor [Homo sapiens]
898 gi 110434001 AK022548.1 unnamed protein product [Homo sapiens ]  898 gi 110434001 AK022548.1 unnamed protein product [Homo sapiens]
899 gi 154792063 NM_003352.4 small ubiquitin-related  899 gi 154792063 NM_003352.4 small ubiquitin-related
modifier 1 isoform a precursor [Homo sapiens]  modifier 1 isoform a precursor [Homo sapiens]
900 gi 183281439 NM_003757.2 eukaryotic translation  900 gi 183281439 NM_003757.2 eukaryotic translation
initiation factor 3 subunit I [Homo sapiens]  initiation factor 3 subunit I [Homo sapiens]
901 gi 133469915 NM_003906.3 80 kDa MCM3-associated protein  901 gi 133469915 NM_003906.3 80 kDa MCM3-associated protein
[Homo sapiens] 902 gi 1195972858 NM_004228.5 cytohesin-2 isoform 2 [Homo sapiens ] [Homo sapiens] 902 gi 1195972858 NM_004228.5 cytohesin-2 isoform 2 [Homo sapiens]
903 gi 142716281 NM_013242.2 transcription factor IIB [Homo sapiens ]  903 gi 142716281 NM_013242.2 transcription factor IIB [Homo sapiens]
904 gi 156676378 NM_016004.2 intraflagellar transport  904 gi 156676378 NM_016004.2 intraflagellar transport
protein 52 homolog [Homo sapiens ]  protein 52 homolog [Homo sapiens]
905 gi 1261490711 NM_138399.4 transmembrane protein 44  905 gi 1261490711 NM_138399.4 transmembrane protein 44
isoform a [Homo sapiens] isoform a [Homo sapiens]
906 gi 141327758 NM_001697.2 ATP synthase subunit 0, 906 gi 141327758 NM_001697.2 ATP synthase subunit 0,
mitochondrial precursor [Homo sapiens ]  mitochondrial precursor [Homo sapiens]
907 gi 1124053441 NM_000934.3 alpha-2-antiplasmin isoform a precursor [Homo sapiens] 907 gi 1124053441 NM_000934.3 alpha-2-antiplasmin isoform a precursor [Homo sapiens]
908 gi 147132573 NM_002733.3 5 ' -AMP-activated protein 908 gi 147132573 NM_002733.3 5'-AMP activated protein
kinase subunit gamma-1 isoform 1 [Homo sapiens]  kinase subunit gamma-1 isoform 1 [Homo sapiens]
909 gi 147132588 NM_002741.3 serine/threonine-protein  909 gi 147132588 NM_002741.3 serine / threonine protein
kinase Nl isoform 2 [Homo sapiens ]  kinase Nl isoform 2 [Homo sapiens]
910 gi 1257196241 NM_001063.3 serotransferrin precursor  910 gi 1257196241 NM_001063.3 serotransferrin precursor
[Homo sapiens]  [Homo sapiens]
911 gi 1205277461 NM_001064.2 transketolase [Homo sapiens] 911 gi 1205277461 NM_001064.2 transketolase [Homo sapiens]
912 gi 1253795505 NM_004699.2 XAP-5 protein [Homo sapiens]912 gi 1253795505 NM_004699.2 XAP-5 protein [Homo sapiens]
913 gi 1115527096 NM_006035.3 serine/threonine-protein 913 gi 1115527096 NM_006035.3 serine / threonine protein
kinase MRCK beta [Homo  kinase MRCK beta [Homo
sapiens ]  sapiens]
914 gi 168161505 NM_005718.3 actin-related protein 2/3  914 gi 168161505 NM_005718.3 actin-related protein 2/3
complex subunit 4 isoform a [Homo sapiens]  complex subunit 4 isoform a [Homo sapiens]
915 gi 1194097343 NM_001114107.2 PDZ and LIM domain protein 3 isoform b [Homo sapiens] 915 gi 1194097343 NM_001114107.2 PDZ and LIM domain protein 3 isoform b [Homo sapiens]
916 gi 132307179 NM_016139.2 coiled-coil-helix-coiled-coil- helix domain-containing protein 2, mitochondrial precursor [Homo sapiens]  916 gi 132307179 NM_016139.2 coiled-coil-helix-coiled-coil-helix domain-containing protein 2, mitochondrial precursor [Homo sapiens]
917 gi 1170932470 NM_024650.3 putative uncharacterized  917 gi 1170932470 NM_024650.3 putative uncharacterized
protein Cllorf80 [Homo  protein Cllorf80 [Homo
sapiens ]  sapiens]
918 gi 1221218971 NM_031209.2 queuine tRNA- ribosyltransferase [Homo sapiens ]  918 gi 1221218971 NM_031209.2 queuin tRNA ribosyltransferase [Homo sapiens]
919 gi 154607109 NM_174929.2 zinc finger MIZ domain- containing protein 2 isoform 2 [Homo sapiens]  919 gi 154607109 NM_174929.2 zinc finger MIZ domain containing protein 2 isoform 2 [Homo sapiens]
920 gi 158761495 NM_001011724.1 heterogeneous nuclear  920 gi 158761495 NM_001011724.1 heterogeneous nuclear
ribonucleoprotein Al-like 2 [Homo sapiens]  ribonucleoprotein Al-like 2 [Homo sapiens]
921 gi 1117956372 NM_001077685.1 arf-GAP with GTPase, ANK  921 gi 1117956372 NM_001077685.1 arf-GAP with GTPase, ANK
repeat and PH domain- containing protein 7 [Homo sapiens ]  repeat and PH domain-containing protein 7 [Homo sapiens]
922 gi 150301237 NM_000637.2 glutathione reductase,  922 gi 150301237 NM_000637.2 glutathione reductase,
mitochondrial isoform 1 precursor [Homo sapiens]  mitochondrial isoform 1 precursor [Homo sapiens]
923 gi 148255890 NM_001001329.1 glucosidase 2 subunit beta  923 gi 148255890 NM_001001329.1 glucosidase 2 subunit beta
isoform 2 [Homo sapiens]  isoform 2 [Homo sapiens]
924 gi 142544245 NM_003009.2 selenoprotein W [Homo sapiens] 924 gi 142544245 NM_003009.2 selenoprotein W [Homo sapiens]
925 gi 16102857 AL122064.1 hypothetical protein [Homo 925 gi 16102857 AL122064.1 hypothetical protein [Homo
sapiens ]  sapiens]
926 gi 1186928845 NM_032476.3 28S ribosomal protein S6,  926 gi 1186928845 NM_032476.3 28S ribosomal protein S6,
mitochondrial [Homo sapiens] 927 gi 119913436 NM_001694.2 V-type proton ATPase 16 kDa proteolipid subunit [Homo sapiens ] mitochondrial [Homo sapiens] 927 gi 119913436 NM_001694.2 V-type proton ATPase 16 kDa proteolipid subunit [Homo sapiens]
928 gi 1205277389 NM_004082.3 dynactin subunit 1 isoform 1  928 g1 1205277389 NM_004082.3 dynactin subunit 1 isoform 1
[Homo sapiens]  [Homo sapiens]
929 gi 155750040 NM_001940.3 atrophin-1 [Homo sapiens] 929 gi 155750040 NM_001940.3 atrophin-1 [Homo sapiens]
930 gi 1156071491 NM_002086.4 growth factor receptor-bound protein 2 isoform 1 [Homo sapiens ] 930 gi 1156071491 NM_002086.4 growth factor receptor-bound protein 2 isoform 1 [Homo sapiens]
931 gi 1194018519 NM_002094.3 eukaryotic peptide chain  931 gi 1194018519 NM_002094.3 eukaryotic peptide chain
release factor GTP-binding subunit ERF3A isoform 1 [Homo sapiens ]  release factor GTP-binding subunit ERF3A isoform 1 [Homo sapiens]
932 gi 141399283 NM_002156.4 60 kDa heat shock protein, mitochondrial [Homo sapiens] 932 gi 141399283 NM_002156.4 60 kDa heat shock protein, mitochondrial [Homo sapiens]
933 gi 1116829963 NM_002256.3 metastasis-suppressor KiSS-1 933 gi 1116829963 NM_002256.3 metastasis suppressor KiSS-1
[Homo sapiens]  [Homo sapiens]
934 gi 1153945727 NM_005909.3 microtubule-associated protein  934 gi 1153945727 NM_005909.3 microtubule-associated protein
1B [Homo sapiens]  1B [Homo sapiens]
935 gi 1189409157 NM_016841.3 microtubule-associated protein tau isoform 4 [Homo sapiens] 935 gi 1189409157 NM_016841.3 microtubule-associated protein tau isoform 4 [Homo sapiens]
936 gi 114043021 NM_004990.2 methionyl-tRNA synthetase, cytoplasmic [Homo sapiens]936 gi 114043021 NM_004990.2 methionyl-tRNA synthetase, cytoplasmic [Homo sapiens]
937 gi 132307122 NM_004576.2 serine/threonine-protein 937 gi 132307122 NM_004576.2 serine / threonine protein
Phosphatase 2A 55 kDa  Phosphatase 2A 55 kDa
regulatory subunit B beta isoform isoform a [Homo sapiens ]  regulatory subunit B beta isoform isoform a [Homo sapiens]
938 gi 122538466 NM_002796.2 proteasome subunit beta type-4  938 gi 122538466 NM_002796.2 proteasome subunit beta type-4
[Homo sapiens]  [Homo sapiens]
939 gi 148762925 NM_005049.2 periodic tryptophan protein 2 homolog [Homo sapiens] 939 gi 148762925 NM_005049.2 periodic tryptophan protein 2 homologous [Homo sapiens]
940 gi 171164881 NM_001013.3 40S ribosomal protein S9 [Homo sapiens ]  940 gi 171164881 NM_001013.3 40S ribosomal protein S9 [Homo sapiens]
941 gi 1171846267 NM_005726.4 elongation factor Ts,  941 gi 1171846267 NM_005726.4 elongation factor Ts,
mitochondrial isoform 2 precursor [Homo sapiens] mitochondrial isoform 2 precursor [Homo sapiens]
942 gi 123238209 NM_005731.2 actin-related protein 2/3 942 gi 123238209 NM_005731.2 actin-related protein 2/3
complex subunit 2 [Homo sapiens ]  complex subunit 2 [Homo sapiens]
943 gi 114971416 NM_005762.2 transcription intermediary  943 gi 114971416 NM_005762.2 transcription intermediary
factor 1-beta [Homo sapiens] factor 1-beta [Homo sapiens]
944 gi 1207028746 NM_006096.3 protein NDRG1 [Homo sapiens]944 gi 1207028746 NM_006096.3 protein NDRG1 [Homo sapiens]
945 gi 122907051 NM_006409.2 actin-related protein 2/3 945 gi 122907051 NM_006409.2 actin-related protein 2/3
complex subunit 1A isoform 1 [Homo sapiens]  complex subunit 1A isoform 1 [Homo sapiens]
946 gi 111055016 AF142569.1 hypothetical protein SBBI23  946 gi 111055016 AF142569.1 hypothetical protein SBBI23
[Homo sapiens]  [Homo sapiens]
947 gi 1112421107 NM_015125.3 protein capicua homolog [Homo sapiens ]  947 gi 1112421107 NM_015125.3 protein capicua homologue [Homo sapiens]
948 gi 156676386 NM_007364.2 transmembrane emp24 domain- containing protein 3 precursor [Homo sapiens]  948 gi 156676386 NM_007364.2 transmembrane emp24 domain containing protein 3 precursor [Homo sapiens]
949 gi 156676313 NM_002568.3 polyadenylate-binding protein  949 gi 156676313 NM_002568.3 polyadenylate-binding protein
1 [Homo sapiens]  1 [Homo sapiens]
950 gi 124431995 NM_020145.2 endophilin-B2 [Homo sapiens] 950 gi 124431995 NM_020145.2 endophilin B2 [Homo sapiens]
951 gi 1141802780 NM_052868.2 Immunoglobulin superfamily 951 gi 1141802780 NM_052868.2 Immunoglobulin superfamily
member 8 [Homo sapiens]  member 8 [Homo sapiens]
952 gi 117149812 NM_057161.2 kelch domain-containing  952 gi 117149812 NM_057161.2 kelch domain-containing
protein 3 isoform 1 [Homo sapiens ]  protein 3 isoform 1 [Homo sapiens]
953 gi 128274700 NM_145806.2 zinc finger protein 511 [Homo sapiens ] 953 gi 128274700 NM_145806.2 zinc finger protein 511 [Homo sapiens]
954 gi 14505488 NM_002539.1 Ornithine decarboxylase [Homo sapiens ]  954 gi 14505488 NM_002539.1 Ornithine decarboxylase [Homo sapiens]
955 gi 178217389 NM_001004.3 60S acidic ribosomal protein  955 gi 178217389 NM_001004.3 60S acidic ribosomal protein
P2 [Homo sapiens]  P2 [Homo sapiens]
956 gi 162739176 NM_002950.3 dolichyl- diphosphooligosaccharide-- protein glycosyltransferase subunit 1 precursor [Homo sapiens ]  956 gi 162739176 NM_002950.3 dolichyldiphosphooligosaccharide-- protein glycosyltransferase subunit 1 precursor [Homo sapiens]
957 gi 1194595508 NM_001130438.1 spectrin alpha chain, brain isoform 1 [Homo sapiens] 957 gi 1194595508 NM_001130438.1 spectrin alpha chain, brain isoform 1 [Homo sapiens]
958 gi 113236578 NM_024330.1 long-chain fatty acid 958 gi 113236578 NM_024330.1 long-chain fatty acid
transport protein 3 [Homo sapiens ]  transport protein 3 [Homo sapiens]
959 gi 1215277016 NM_001142370.1 tyrosine-protein Phosphatase non-receptor type 18 isoform 2 [Homo sapiens]  959 gi 1215277016 NM_001142370.1 tyrosine protein phosphatase non-receptor type 18 isoform 2 [Homo sapiens]
960 gi 1194018569 NM_017918.4 coiled-coil domain-containing protein 109B [Homo sapiens] 960 gi 1194018569 NM_017918.4 coiled-coil domain-containing protein 109B [Homo sapiens]
961 gi 1256818771 NM_018285.3 U3 small nucleolar 961 gi 1256818771 NM_018285.3 U3 small nucleolar
ribonucleoprotein protein IMP3 [Homo sapiens]  ribonucleoprotein protein IMP3 [Homo sapiens]
962 gi 1209976985 NM_018386.2 PCI domain-containing protein  962 gi 1209976985 NM_018386.2 PCI domain-containing protein
2 [Homo sapiens]  2 [Homo sapiens]
963 gi 1113722119 NM_032119.3 G-protein coupled receptor 98 precursor [Homo sapiens] 963 gi 1113722119 NM_032119.3 G-protein coupled receptor 98 precursor [Homo sapiens]
964 gi 110438604 AK025936.1 unnamed protein product [Homo sapiens ] 964 gi 110438604 AK025936.1 unnamed protein product [Homo sapiens]
965 gi 150234894 NM_173473.2 anaphase-promoting complex  965 gi 150234894 NM_173473.2 anaphase-promoting complex
subunit 16 isoform 1 [Homo sapiens ] subunit 16 isoform 1 [Homo sapiens]
966 gi 1207028465 NM_005566.3 L-lactate dehydrogenase A  966 g1 1207028465 NM_005566.3 L-lactate dehydrogenase A
chain isoform 1 [Homo sapiens] chain isoform 1 [Homo sapiens]
967 gi 1194440683 NM_002337.2 alpha-2-macroglobulin 967 gi 1194440683 NM_002337.2 alpha-2-macroglobulin
receptor-associated protein precursor [Homo sapiens]  receptor-associated protein precursor [Homo sapiens]
968 gi 133356548 NM_002388.3 DNA replication licensing  968 gi 133356548 NM_002388.3 DNA replication licensing
factor MCM3 [Homo sapiens] factor MCM3 [Homo sapiens]
969 gi 128193181 BX248001.1 unnamed protein product [Homo sapiens ] 969 gi 128193181 BX248001.1 unnamed protein product [Homo sapiens]
970 gi 133598947 NM_002660.2 1-phosphatidylinositol-4 , 5- bisphosphate Phosphodiesterase gamma-1 isoform a [Homo sapiens ]  970 gi 133598947 NM_002660.2 1-phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma-1 isoform a [Homo sapiens]
971 gi 1223468675 NM_021975.3 transcription factor p65  971 gi 1223468675 NM_021975.3 transcription factor p65
isoform 1 [Homo sapiens]  isoform 1 [Homo sapiens]
972 gi 149640008 NM_003316.3 E3 ubiquitin-protein ligase  972 gi 149640008 NM_003316.3 E3 ubiquitin protein ligase
TTC3 [Homo sapiens]  TTC3 [Homo sapiens]
973 gi 1166064032 NM_145735.2 rho guanine nucleotide  973 gi 1166064032 NM_145735.2 rho guanine nucleotide
exchange factor 7 isoform b [Homo sapiens]  exchange factor 7 isoform b [Homo sapiens]
974 gi 183716023 NM_017596.2 kinesin-like protein KIF21B  974 gi 183716023 NM_017596.2 kinesin-like protein KIF21B
[Homo sapiens]  [Homo sapiens]
975 gi 1109148507 NM_017670.2 ubiquitin thioesterase OTUBl  975 gi 1109148507 NM_017670.2 ubiquitin thioesterase OTUBl
[Homo sapiens]  [Homo sapiens]
976 gi 111034854 NM_020644.1 transmembrane protein 9B  976 gi 111034854 NM_020644.1 transmembrane protein 9B
precursor [Homo sapiens]  precursor [Homo sapiens]
977 gi 150345990 NM_001001975.1 ATP synthase subunit delta, mitochondrial precursor [Homo sapiens ]  977 gi 150345990 NM_001001975.1 ATP synthase subunit delta, mitochondrial precursor [Homo sapiens]
978 gi 1145580576 NM_001329.2 C-terminal-binding protein 2 isoform 1 [Homo sapiens]978 gi 1145580576 NM_001329.2 C-terminal-binding protein 2 isoform 1 [Homo sapiens]
979 gi 1226958667 NM_004107.4 IgG receptor FcRn large 979 gi 1226958667 NM_004107.4 IgG receptor FcRn large
subunit p51 precursor [Homo sapiens ]  subunit p51 precursor [Homo sapiens]
980 gi 151476153 CR749210.1 hypothetical protein [Homo sapiens ]  980 gi 151476153 CR749210.1 hypothetical protein [Homo sapiens]
981 gi 1193082959 NM_014487.4 zinc finger protein 330 [Homo sapiens ]  981 gi 1193082959 NM_014487.4 zinc finger protein 330 [Homo sapiens]
982 gi 1156416004 NM_014186.3 COMM domain-containing protein  982 gi 1156416004 NM_014186.3 COMM domain-containing protein
9 isoform 1 [Homo sapiens]  9 isoform 1 [Homo sapiens]

Claims

Patentansprüche claims
1. Verfahren zur Identifizierung von Markersequenzen für Brustkrebs dadurch gekennzeichnet, dass a. Markersequenz-Kandidaten für Brustkrebs dadurch A method for identifying marker sequences for breast cancer, characterized in that a. Marker sequence candidates for breast cancer by
identifiziert werden, dass ein Träger, auf dem mindestens 1.000 unterschiedliche Proteine immobilisiert sind, mit einer Serumprobe einer Patientin mit Brustkrebs in Kontakt gebracht wird und Proteine identifiziert werden, die mit dem Serum eine Wechselwirkung zeigen (Markersequenz-Kandidaten) , und b. die Wechselwirkung von einem oder mehreren Markersequenz- Kandidaten aus a. mit dem Serum von Patientinnen mit identifying a carrier on which at least 1,000 different proteins are immobilized being contacted with a serum sample from a breast cancer patient and identifying proteins that interact with the serum (marker sequence candidates), and b. the interaction of one or more marker sequence candidates from a. with the serum of patients with
Brustkrebs bestimmt wird im Vergleich zu der Wechselwirkung des / der Markersequenz-Kandidaten aus a. mit dem Serum von Patientinnen mit benignen Veränderungen und der Wechselwirkung des / der Markersequenz-Kandidaten aus a. mit dem Serum von gesunden Kontrollpersonen, und c. Markersequenzen dadurch identifiziert werden, dass sie mit dem Serum von Patientinnen mit Brustkrebs eine andere Breast cancer is determined in comparison to the interaction of the marker sequence candidate from a. with the serum of patients with benign alterations and the interaction of the marker sequence candidate from a. with serum from healthy controls, and c. Marker sequences are identified by being different with the serum from breast cancer patients
Wechselwirkung zeigen als mit dem Serum von Patientinnen mit benignen Veränderungen und dem Serum von gesunden Interaction show as with the serum of patients with benign changes and the serum of healthy
Kontrollpersonen und wobei die Auswertung mittels Controllers and the evaluation by means of
statistischer Analyse erfolgt. statistical analysis.
2. Verfahren nach Anspruch 1 dadurch gekennzeichnet, dass die Markersequenzen spezifisch sind für Brustkrebs mit einem hohen2. The method according to claim 1, characterized in that the marker sequences are specific for breast cancer with a high
Risiko der Metastasenbildung. Risk of metastasis.
3. Markersequenz für Brustkrebs erhältlich durch ein 3. Marker sequence for breast cancer available through
Verfahren nach einem der Ansprüche 1 oder 2 und ausgewählt aus den Sequenzen umfassend SEQ ID o. 1 - 1473 und Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise 95 % der Länge der Sequenzen SEQ ID No. 1 - 1473 und Homologen von SEQ ID No . 1- 1473 und deren Teilsequenzen mit einer Identität von mindestens 95%, vorzugsweise 98 % oder mehr zu den Method according to one of claims 1 or 2 and selected from the sequences comprising SEQ ID o. 1-1473 and partial sequences of SEQ ID No. 1-1473 with at least 90%, preferably 95% of the length of the sequences SEQ ID NO. 1 - 1473 and homologs of SEQ ID No. 1-1473 and their partial sequences with an identity of at least 95%, preferably 98% or more to the
entsprechenden Nukleinsäure- und/oder Proteinsequenzen und Sequenzen kodiert durch SEQ ID No . 1 - 491, Teilsequenzen davon sowie deren Homologe. corresponding nucleic acid and / or protein sequences and sequences encoded by SEQ ID No. 1 - 491, partial sequences thereof and their homologues.
4. Anordnung von Markersequenzen für Brustkrebs umfassend eine oder mehrere Markersequenzen nach Anspruch 3. 4. Arrangement of marker sequences for breast cancer comprising one or more marker sequences according to claim 3.
5. Proteinarray umfassend eine oder mehrere Markersequenzen nach Anspruch 3. 5. A protein array comprising one or more marker sequences according to claim 3.
6. Diagnostikum umfassend eine oder mehrere Markersequenzen nach Anspruch 3 und gegebenenfalls weitere Zusatz- und/oder Hilfsstoffe. 6. diagnostic agent comprising one or more marker sequences according to claim 3 and optionally further additives and / or adjuvants.
7. Test Kit umfassend eine oder mehrere Markersequenzen nach Anspruch 3 und gegebenenfalls weitere Zusatz- und/oder 7. Test kit comprising one or more marker sequences according to claim 3 and optionally further additional and / or
Hilfsstoffe . Auxiliaries.
8. Anordnung nach Anspruch 4, Proteinarray nach Anspruch 5, Diagnostikum nach Anspruch 6, Test Kit nach Anspruch 7, dadurch gekennzeichnet, dass 2 oder 3, vorzugsweise 4 oder 5, besonders bevorzugt 7 oder 8 oder mehr unterschiedliche 8. Arrangement according to claim 4, protein array according to claim 5, diagnostic according to claim 6, test kit according to claim 7, characterized in that 2 or 3, preferably 4 or 5, more preferably 7 or 8 or more different
MarkerSequenzen für Brustkrebs gleichzeitig verwendet werden. Marker sequences for breast cancer are used simultaneously.
9. Verwendung einer oder mehrerer Markersequenzen nach 9. Use of one or more marker sequences according to
Anspruch 3, einer Anordnung nach Anspruch 4 oder 8, einesClaim 3, an arrangement according to claim 4 or 8, a
Proteinarrays nach Anspruch 5 oder 8, eines Diagnostikums nach Anspruch 6 oder 8 oder eines Test Kits nach Anspruch 7 oder 8 zur Früherkennung, Diagnose, Prognose, Therapiesteuerung und/oder Nachsorge bei Brustkrebs. Protein arrays according to claim 5 or 8, a diagnostic agent according to claim 6 or 8 or a test kit according to claim 7 or 8 for the early detection, diagnosis, prognosis, therapy control and / or aftercare in breast cancer.
10. Verwendung einer oder mehrerer Markersequenzen nach 10. Use of one or more marker sequences according to
Anspruch 3, einer Anordnung nach Anspruch 4 oder 8, eines Proteinarrays nach Anspruch 5 oder 8, eines Diagnostikums nach Anspruch 6 oder 8 oder eines Test Kits nach Anspruch 7 oder 8 zur Unterscheidung von Brustkrebs von benignen Veränderungen. Claim 3, an arrangement according to claim 4 or 8, a protein array according to claim 5 or 8, a diagnostic kit according to claim 6 or 8 or a test kit according to claim 7 or 8 for distinguishing breast cancer from benign changes.
11. Verwendung einer oder mehrerer Markersequenzen nach 11. Use of one or more marker sequences according to
Anspruch 3, einer Anordnung nach Anspruch 4 oder 8, eines Proteinarrays nach Anspruch 5 oder 8, eines Diagnostikums nach Anspruch 6 oder 8 oder eines Test Kits nach Anspruch 7 oder 8 zur individualisierten Diagnostik und/oder Therapie bei einzelnen Patienten, Patientengruppen, Kohorten, Claim 3, an arrangement according to claim 4 or 8, a protein array according to claim 5 or 8, a diagnostic kit according to claim 6 or 8 or a test kit according to claim 7 or 8 for individualized diagnosis and / or therapy in individual patients, patient groups, cohorts,
Bevölkerungsgruppen, Varianten von Brustkrebs, Stadien von Brustkrebs . Populations, variants of breast cancer, stages of breast cancer.
12. Verwendung einer oder mehrerer Markersequenzen nach 12. Use of one or more marker sequences according to
Anspruch 3, einer Anordnung nach Anspruch 4 oder 8, eines Proteinarrays nach Anspruch 5 oder 8, eines Diagnostikums nach Anspruch 6 oder 8 oder eines Test Kits nach Anspruch 7 oder 8 zum Nachweis und/oder zur Bestimmung der Menge von einem oder mehreren Autoantikörpern die mit Brustkrebs assoziiert sind, beispielsweise in Körperflüssigkeit oder Gewebe eines Claim 3, an arrangement according to claim 4 or 8, a protein array according to claim 5 or 8, a diagnostic kit according to claim 6 or 8 or a test kit according to claim 7 or 8 for detecting and / or determining the amount of one or more autoantibodies associated with breast cancer, for example, in body fluid or tissue of a
Patienten . Patients.
13. Verwendung einer oder mehrerer Markersequenzen nach 13. Use of one or more marker sequences according to
Anspruch 3, einer Anordnung nach Anspruch 4 oder 8, eines Proteinarrays nach Anspruch 5 oder 8, eines Diagnostikums nach Anspruch 6 oder 8 oder eines Test Kits nach Anspruch 7 oder 8 zur Analyse von Autoantikörperprofilen von Patienten, Claim 3, an arrangement according to claim 4 or 8, a protein array according to claim 5 or 8, a diagnostic kit according to claim 6 or 8 or a test kit according to claim 7 or 8 for the analysis of autoantibody profiles of patients,
insbesondere zur qualitativen und/oder quantitativen Analyse von Autoantikörpern und/oder zur Überwachung von Veränderungen von Autoantikörperprofilen, beispielsweise in Körperflüssigkeiten wie Serum, Gewebe oder Gewebeauszügen des Patienten . in particular for the qualitative and / or quantitative analysis of autoantibodies and / or for monitoring changes in autoantibody profiles, for example in Body fluids such as serum, tissue or tissue extracts of the patient.
14. Verwendung einer oder mehrerer Markersequenzen nach 14. Use of one or more marker sequences according to
Anspruch 3, einer Anordnung nach Anspruch 4 oder 8, eines Proteinarrays nach Anspruch 5 oder 8, eines Diagnostikums nach Anspruch 6 oder 8 oder eines Test Kits nach Anspruch 7 oder 8 zum Screenen von Substanzen (Wirkstoffen) für Brustkrebs. Claim 3, an arrangement according to claim 4 or 8, a protein array according to claim 5 or 8, a diagnostic kit according to claim 6 or 8 or a test kit according to claim 7 or 8 for screening substances (drugs) for breast cancer.
15. Target zur Behandlung und / oder Therapie von Brustkrebs ausgewählt aus den Markersequenzen nach Anspruch 3. 15. Target for the treatment and / or therapy of breast cancer selected from the marker sequences according to claim 3.
16. Verfahren zur Früherkennung, Diagnose, Prognose, 16. Method for Early Detection, Diagnosis, Prognosis
Therapiesteuerung und/oder Nachsorge bei Brustkrebs wobei a. ) eine oder mehrere Markersequenz (en) ausgewählt aus der Gruppe umfassend die Sequenzen SEQ ID No. 1 - 1473 und  Therapy control and / or aftercare for breast cancer where a. ) one or more marker sequence (s) selected from the group comprising the sequences SEQ ID NO. 1 - 1473 and
Teilsequenzen von SEQ ID No . 1 - 1473 mit mindestens 90 %, vorzugsweise 95 % der Länge der Sequenzen SEQ ID No . 1 - 1473 und Homologen von SEQ ID No . 1- 1473 und deren Teilsequenzen mit einer Identität von mindestens 95%, vorzugsweise 98 % oder mehr zu den entsprechenden Nukleinsäure- und/oder Partial sequences of SEQ ID No. 1 to 1473 with at least 90%, preferably 95% of the length of the sequences SEQ ID No. 1 - 1473 and homologs of SEQ ID No. 1-1473 and their partial sequences with an identity of at least 95%, preferably 98% or more to the corresponding nucleic acid and / or
Proteinsequenzen und Sequenzen kodiert durch SEQ ID No. 1 - 491, Teilsequenzen davon sowie deren Homologe auf einen Träger aufgebracht wird/werden, b. ) mit Körperflüssigkeit oder Gewebeauszug eines Patienten in Kontakt gebracht wird/werden und c.) der Nachweis einer Wechselwirkung der Körperflüssigkeit oder des Gewebeauszugs mit der/den Markersequenz (en) für Protein sequences and sequences encoded by SEQ ID no. 1 - 491, partial sequences thereof and their homologues are applied to a carrier, b. ) is brought into contact with body fluid or tissue extract of a patient, and c.) the detection of an interaction of the body fluid or the tissue extract with the marker sequence (s) for
Brustkrebs aus a.) erfolgt. Breast cancer from a.) Is done.
EP12818894.3A 2011-12-22 2012-12-24 Marker sequences for breast cancer and the use thereof Withdrawn EP2795332A2 (en)

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