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US20200332364A1 - Compositions and methods for detection of diseases related to exposure to inhaled carcinogens - Google Patents

Compositions and methods for detection of diseases related to exposure to inhaled carcinogens Download PDF

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US20200332364A1
US20200332364A1 US16/611,628 US201816611628A US2020332364A1 US 20200332364 A1 US20200332364 A1 US 20200332364A1 US 201816611628 A US201816611628 A US 201816611628A US 2020332364 A1 US2020332364 A1 US 2020332364A1
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interleukin
disease
receptor
nucleic acid
protein
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Walter Joseph Jessen
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Labcorp Holdings Inc
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06F—ELECTRIC DIGITAL DATA PROCESSING
    • G06F16/00—Information retrieval; Database structures therefor; File system structures therefor
    • G06F16/20—Information retrieval; Database structures therefor; File system structures therefor of structured data, e.g. relational data
    • G06F16/21—Design, administration or maintenance of databases
    • G06F16/215—Improving data quality; Data cleansing, e.g. de-duplication, removing invalid entries or correcting typographical errors
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06F—ELECTRIC DIGITAL DATA PROCESSING
    • G06F16/00—Information retrieval; Database structures therefor; File system structures therefor
    • G06F16/20—Information retrieval; Database structures therefor; File system structures therefor of structured data, e.g. relational data
    • G06F16/24—Querying
    • G06F16/245—Query processing
    • G06F16/2458—Special types of queries, e.g. statistical queries, fuzzy queries or distributed queries
    • G06F16/2465—Query processing support for facilitating data mining operations in structured databases
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06F—ELECTRIC DIGITAL DATA PROCESSING
    • G06F16/00—Information retrieval; Database structures therefor; File system structures therefor
    • G06F16/90—Details of database functions independent of the retrieved data types
    • G06F16/901—Indexing; Data structures therefor; Storage structures
    • G06F16/9024—Graphs; Linked lists
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
    • G16B50/30—Data warehousing; Computing architectures
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G01N2800/122—Chronic or obstructive airway disorders, e.g. asthma COPD
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

  • LC lung cancer
  • COPD chronic obstructive pulmaonary disease
  • CVD cardiovascular disease
  • LC lung cancer
  • COPD chronic obstructive pulmaonary disease
  • CVD cardiovascular disease
  • a method to detect biomarkers associated with at least one of lung cancer (LC) in an individual comprising the steps of: obtaining a sample from the individual; and measuring the amount of the marker, and/or the amount, or a mutation in, a nucleic acid (e.g.
  • genomic DNA or mRNA that encodes for, or regulates expression of, the gene for at least one of anaplastic lymphoma receptor tyrosine kinase (ALK), B-cell CLL/lymphoma 2 (BCL2), baculoviral IAP repeat containing 5 (BIRC5), B-Raf proto-oncogene, serine/threonine kinase (BRAF), CD274 molecule (CD274), cadherin 1 (CDH1), cyclin-dependent kinase inhibitor 2A (CDKN2A), carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5), chitinase 3 like 1 (CHI3L1), cholinergic receptor nicotinic alpha 5 subunit (CHRNA5), CLPTM1-like (CLPTM1L), catechol-O-methyltransferase (COMT), catenin beta 1 (CTNNB1), C-X-C motif chemokine
  • ABO blood group transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase
  • ABO angiotensin I converting enzyme 2
  • ACE2 angiotensinogen
  • APLN apelin
  • APOA1 apolipoprotein A1
  • APOA2 apolipoprotein A2
  • APOB apolipoprotein B
  • APOE apolipoprotein E
  • caspase 1 caspase 1
  • CD36 molecule CD36
  • C-reactive protein C-reactive protein
  • CRP pentraxin-related
  • CRP pentraxin-related
  • ELL elongation factor for RNA polymerase II
  • F2 intercellular adhesion molecule 1
  • IAM1 interleukin 1 beta
  • the method may include measurement of at least one normalization (e.g., housekeeping gene). Or, measurement of various combinations of these markers may be performed.
  • at least one normalization e.g., housekeeping gene
  • a typical immunoglobulin (antibody) structural unit is known to comprise a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms “variable light chain” (VL) and “variable heavy chain” (VH) refer to these light and heavy chains respectively.
  • An antibody can be specific for a particular antigen.
  • the antibody or its antigen can be either an analyte or a binding partner.
  • Antibodies exist as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases.
  • pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond.
  • the F(ab)′2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab′)2 dimer into an Fab′ monomer.
  • the Fab′ monomer is essentially an Fab with part of the hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y.
  • a single chain Fv (“scFv”) polypeptide is a covalently linked VH::VL heterodimer which may be expressed from a nucleic acid including VH- and VL-encoding sequences either joined directly or joined by a peptide-encoding linker.
  • VH- and VL-encoding sequences either joined directly or joined by a peptide-encoding linker.
  • Allele specific primer extension refers to a mutation detection method utilizing primers which hybridize to a corresponding DNA sequence and which are extended depending on the successful hybridization of the 3′ terminal nucleotide of such primer.
  • extension primers that possess a 3′ terminal nucleotide which form a perfect match with the target sequence are extended to form extension products.
  • Modified nucleotides can be incorporated into the extension product, such nucleotides effectively labeling the extension products for detection purposes.
  • an extension primer may instead comprise a 3′ terminal nucleotide which forms a mismatch with the target sequence. In this instance, primer extension does not occur unless the polymerase used for extension inadvertently possesses exonuclease activity.
  • asymmetric PCR may be used to amplify predominantly or exclusively a single stranded product as is well known in the art (e.g., Poddar, Molec. And Cell. Probes 14:25-32 (2000)). This can be achieved using each pair of primers by reducing the concentration of one primer significantly relative to the other primer of the pair (e.g., 100 fold difference). Amplification by asymmetric PCR is generally linear. A skilled artisan will understand that different amplification methods may be used together.
  • control has its art-understood meaning of being a standard against which results are compared. Typically, controls are used to augment integrity in experiments by isolating variables in order to make a conclusion about such variables.
  • a control is a reaction or assay that is performed simultaneously with a test reaction or assay to provide a comparator. In one experiment, the “test” (i.e., the variable being tested) is applied. In the second experiment, the “control,” the variable being tested is not applied.
  • a control is a historical control (i.e., of a test or assay performed previously, or an amount or result that is previously known).
  • a control is or comprises a printed or otherwise saved record. A control may be a positive control or a negative control.
  • deletion encompasses a mutation that removes one or more nucleotides from a naturally-occurring nucleic acid.
  • Epitope refers to a fragment or portion of a molecule or a molecule compound (e.g., a polypeptide or a protein complex) that makes contact with a particular antibody or antibody like proteins.
  • exon is a nucleic acid sequence that is found in mature or processed RNA after other portions of the RNA (e.g., intervening regions known as introns) have been removed by RNA splicing. As such, exon sequences generally encode for proteins or portions of proteins.
  • An intron is the portion of the RNA that is removed from surrounding exon sequences by RNA splicing.
  • a reagent may be directly or indirectly labeled with a detectable substance.
  • the detectable substance may be, for example, selected, e.g., from a group consisting of radioisotopes, fluorescent compounds, enzymes, and enzyme co-factor. Methods of labeling antibodies are well known in the art.
  • Flanking is meant that a primer hybridizes to a target nucleic acid adjoining a region of interest sought to be amplified on the target.
  • preferred primers are pairs of primers that hybridize 3′ from a region of interest, one on each strand of a target double stranded DNA molecule, such that nucleotides may be add to the 3′ end of the primer by a suitable DNA polymerase.
  • primers that flank mutant sequences do not actually anneal to the mutant sequence but rather anneal to a sequence that adjoins the mutant sequence.
  • primers that flank an exon are generally designed not to anneal to the exon sequence but rather to anneal to sequence that adjoins the exon (e.g. intron sequence). However, in some cases, amplification primer may be designed to anneal to the exon sequence.
  • identity refers to sequence identity between two amino acid sequences or between two nucleic acid sequences. Percent identity can be determined by aligning two sequences and refers to the number of identical residues (i.e., amino acid or nucleotide) at positions shared by the compared sequences. Sequence alignment and comparison may be conducted using the algorithms standard in the art (e.g. Smith and Waterman, 1981, Adv. Appl. Math. 2:482; Needleman and Wunsch, 1970, J. Mol. Biol. 48:443; Pearson and Lipman, 1988, Proc. Natl. Acad.
  • in vivo refers to events that occur within a multi-cellular organism such as a human or a non-human animal.
  • Labeled proteins and peptides can be prepared by incorporation of, or conjugation to, a label that is detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, chemical or other means.
  • a label or labeling moiety may be directly detectable (i.e., it does not require any further reaction or manipulation to be detectable, e.g., a fluorophore is directly detectable) or it may be indirectly detectable (i.e., it is made detectable through reaction or binding with another entity that is detectable, e.g., a hapten is detectable by immunostaining after reaction with an appropriate antibody comprising a reporter such as a fluorophore).
  • the primary transcript can be cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nucleotide stem-loop precursor miRNA (pre-miRNA), which can further be cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products.
  • pre-miRNA a RNA-induced silencing complex
  • RISC RNA-induced silencing complex
  • Mutation and/or variant As used herein, the terms mutation and variant are used interchangeably to describe a nucleic acid or protein sequence change.
  • the term “mutant” as used herein refers to a mutated, or potentially non-functional form of a gene. The term includes any mutation that renders a gene not functional from a point mutation to large chromosomal rearrangements as is known in the art.
  • Polypeptide or protein refers to a polymer of amino acids, and not to a specific length. Thus, peptides, oligopeptides and proteins are included within the definition of polypeptide and/or protein. “Polypeptide” and “protein” are used interchangeably herein to describe protein molecules that may comprise either partial or full-length proteins. The term “peptide” is used to denote a less than full-length protein or a very short protein unless the context indicates otherwise.
  • proteins As is known in the art, “proteins”, “peptides,” “polypeptides” and “oligopeptides” are chains of amino acids (typically L-amino acids) whose alpha carbons are linked through peptide bonds formed by a condensation reaction between the carboxyl group of the alpha carbon of one amino acid and the amino group of the alpha carbon of another amino acid.
  • amino acids making up a protein are numbered in order, starting at the amino terminal residue and increasing in the direction toward the carboxy terminal residue of the protein.
  • Abbreviations for amino acid residues are the standard 3-letter and/or 1-letter codes used in the art to refer to one of the 20 common L-amino acids.
  • the term “specific,” when used in connection with an oligonucleotide primer, refers to an oligonucleotide or primer, which under appropriate hybridization or washing conditions, is capable of hybridizing to the target of interest and not substantially hybridizing to nucleic acids which are not of interest. Higher levels of sequence identity are preferred and include at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence identity.
  • Solid support means a structure that provides a substrate onto which biomolecules may be bound.
  • a solid support may be an assay well (i.e., such as a microtiter plate), or the solid support may be a location on an array, or a mobile support, such as a bead.
  • the disclosure herein provides novel mutations identified in a disease and/or syndrome of interest gene that can be used for more accurate diagnosis of disorders relating to the gene and/or syndrome of interest.
  • the sample contains nucleic acid.
  • the testing step comprises nucleic acid sequencing.
  • the testing step comprises hybridization.
  • the hybridization is performed using one or more oligonucleotide probes specific for a region in the biomarker of interest.
  • hybridization is performed under conditions sufficiently stringent to disallow a single nucleotide mismatch.
  • the hybridization is performed with a microarray.
  • the testing step comprises restriction enzyme digestion.
  • the testing step comprises PCR amplification.
  • the PCR amplification is digital PCR amplification.
  • the testing step comprises primer extension.
  • the primer extension is single-base primer extension.
  • the testing step comprises performing a multiplex allele-specific primer extension (ASPE).
  • ASPE multiplex allele-specific primer extension
  • genomic DNA or mRNA that encodes for, or regulates expression of, the gene for at least one of anaplastic lymphoma receptor tyrosine kinase (ALK), B-cell CLL/lymphoma 2 (BCL2), baculoviral IAP repeat containing 5 (BIRC5), B-Raf proto-oncogene, serine/threonine kinase (BRAF), CD274 molecule (CD274), cadherin 1 (CDH1), cyclin-dependent kinase inhibitor 2A (CDKN2A), carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5), chitinase 3 like 1 (CHI3L1), cholinergic receptor nicotinic alpha 5 subunit (CHRNA5), CLPTM1-like (CLPTM1L), catechol-O-methyltransferase (COMT), catenin beta 1 (CTNNB1), C-X-C motif chemokine
  • a method to detect biomarkers associated with chronic obstructive pulmaonary disease (COPD) in an individual comprising the steps of: obtaining a sample from the individual; and measuring the amount of the marker, and/or the amount and/or a mutation, in a nucleic acid (e.g.
  • COPD chronic obstructive pulmaonary disease
  • ABO blood group transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase
  • ABO angiotensin I converting enzyme 2
  • ACE2 angiotensinogen
  • APLN apelin
  • APOA1 apolipoprotein A1
  • APOA2 apolipoprotein A2
  • APOB apolipoprotein B
  • APOE apolipoprotein E
  • caspase 1 caspase 1
  • CD36 molecule CD36
  • C-reactive protein C-reactive protein
  • CRP pentraxin-related
  • CRP pentraxin-related
  • ELL elongation factor for RNA polymerase II
  • F2 intercellular adhesion molecule 1
  • IAM1 interleukin 1 beta
  • the sample comprises blood, serum, plasma, cell-free nucleic acid (e.g., DNA or RNA), or a liquid or tissue biopsy.
  • cell-free nucleic acid e.g., DNA or RNA
  • the disclosure provides a method to detect the presence of, or susceptibility to a disease associated with exposure to an inhaled carcinogen in an individual.comprising:obtaining a sample from the individual; measuring the amount of at least one marker associated with at least one of lung cancer (LC), chronic obstructive pulmaonary disease (COPD), and/or cardiovascular disease (CVD), in the sample; and comparing the expression of, and/or the presence of a mutation in a gene for, the at least one of lung cancer (LC), chronic obstructive pulmaonary disease (COPD), and/or cardiovascular disease (CVD) in the sample with a control value for each of the markers.
  • LC lung cancer
  • COPD chronic obstructive pulmaonary disease
  • CVD cardiovascular disease
  • control value is determined from a healthy individual or individuals with no detected or detectable lung or cardiovascular pathology.
  • control is a disease control.
  • disease controls may include individuals with lung or heart disease that is not related to exposure to an inhaled carcinogen.
  • the method may comprise detecting biomarkers associated with chronic obstructive pulmaonary disease (COPD) in an individual comprising the steps of: obtaining a sample from the individual; and measuring the amount of the marker, and/or the amount and/or a mutation in a nucleic acid (e.g.
  • COPD chronic obstructive pulmaonary disease
  • the method may comprise detecting biomarkers associated with cardovascular disease (CVD) in an individual comprising the steps of: obtaining a sample from the individual; and measuring the amount of the marker, and/or the amount and/or a mutation in a nucleic acid (e.g.
  • CVD cardovascular disease
  • the composition may include reagents for the measurement of at least one normalization (e.g., housekeeping) gene.
  • the housekeeping gene may be glyceraldehyde 3-phosphate dehydrogenase.
  • other house keeping genes may be used.
  • measurement of various combinations of these markers may be performed.
  • the composition may comprise reagents for measuring the value of the markers of interest in a control.
  • the control value is determined from a healthy individual or individuals with no detected or detectable lung or cardiovascular pathology.
  • the control is a disease control.
  • Such disease controls may include individuals with lung or heart disease that is not related to exposure to an inhaled carcinogen.
  • kits or reagents comprise instructions or other information and/or computer-readable media comprising instructions and/or other information for performing the methods independent of a kit or reagents therein.
  • Antibodies against particular epitopes, polypeptides, and/or proteins can be generated using any of a variety of known methods in the art.
  • the epitope, polypeptide, or protein against which an antibody is desired can be produced and injected into an animal, typically a mammal (such as a donkey, mouse, rabbit, horse, chicken, etc.), and antibodies produced by the animal can be collected from the animal.
  • Monoclonal antibodies can also be produced by generating hybridomas that express an antibody of interest with an immortal cell line.
  • antibodies are labeled with a detectable moiety as described herein.
  • the biomarker may be allowed to complex with a first binding agent (e.g., primary antibody specific for the biomarker and labeled with detectable moiety) and a second binding agent (e.g., a secondary antibody that recognizes the primary antibody or a second primary antibody), where the second binding agent is complexed to a third binding agent (e.g., biotin) that can then interact with a capture support (e.g., magnetic bead) having a reagent (e.g., streptavidin) that recognizes the third binding agent linked to the capture support.
  • the complex (labeled primary antibody: biomarker: second primary antibody-biotin: streptavidin-bead may then be captured using a magnet (e.g., a magnetic probe) to measure the amount of the complex.
  • the variant may comprise a nucleic acid sequence that encompasses at least one of the following: (1) A-to-I editing sites; (2) splice sites; (3) conserved functional RNA structures; (4) validated transcription factor binding sites (TFBS); (5) microRNA (miRNA) binding sites; (6) polyadenylation sites; (7) known regulatory elements; (8) miRNA genes; (9) small nucleolar RNA genes encoded in the ROIs; and/or (10) ultra-conserved elements across placental mammals.
  • TFBS validated transcription factor binding sites
  • two complementary reactions are used.
  • One reaction employs a primer specific for the wild type allele (“wild-type-specific reaction”) and the other reaction employs a primer for the mutant allele (“mutant-specific reaction”).
  • the two reactions may employ a common second primer.
  • PCR primers specific for a particular allele e.g., the wild-type allele or mutant allele
  • the mismatch may be located at/near the 3′ end of the primer, leading to preferential amplification of the perfectly matched allele. Whether an amplification product can be detected from one or in both reactions indicates the absence or presence of the mutant allele.
  • primer extension can be combined with mass spectrometry for accurate and fast detection of the presence or absence of a mutation. See, U.S. Pat. No. 5,885,775 to Haff et al. (analysis of single nucleotide polymorphism analysis by mass spectrometry); U.S. Pat. No. 7,501,251 to Koster (DNA diagnosis based on mass spectrometry); the teachings of both of which are incorporated herein by reference.
  • oligonucleotide probes vary from 15 to 90, 15 to 80, 15 to 70, 15 to 60, 15 to 50, 15 to 40, 15 to 35, 15 to 30, 18 to 30, or 18 to 26 nucleotides in length.
  • the optimal length of an oligonucleotide probe may depend on the particular methods and/or conditions in which the oligonucleotide probe may be employed.
  • nucleic acid probes are useful as primers, e.g., for nucleic acid amplification and/or extension reactions.
  • the gene sequence being evaluated for a variant comprises the exon sequences.
  • the exon sequence and additional flanking sequence e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or more nucleotides of UTR and/or intron sequence
  • intron sequences or other non-coding regions may be evaluated for potentially deleterious mutations.
  • portions of these sequences may be used.
  • Such variant gene sequences may include sequences having at least one of the mutations as described herein.
  • the method may comprise obtaining a nucleic acid from a tissue or body fluid sample from a subject and sequencing at least a portion of a nucleic acid in order to obtain a sample nucleic acid sequence for at least one gene.
  • the method may comprise comparing the variant to known variants associated with a disease associated with exosure to inhaled carcinogens and determining whether the variant is a variant that has been previously identified as being associated with a disease associated with exosure to inhaled carcinogens.
  • the method may comprise identifying the variant as a new, previously uncharacterized variant.
  • next generation may be used.
  • Sanger sequencing may be used.
  • a combination of next-generation (massively-parallel sequencing) and Sanger sequencing may be used.
  • the sequencing comprises at least one of single-molecule sequencing-by-synthesis.
  • a plurality of DNA samples are analyzed in a pool to identify samples that show a variation.
  • a plurality of DNA samples are analyzed in a plurality of pools to identify an individual sample that shows the same variation in at least two pools.
  • sequencing of the nucleic acid is accomplished by massively parallel sequencing (also known as “next generation sequencing”) of single-molecules or groups of largely identical molecules derived from single molecules by amplification through a method such as PCR.
  • massively parallel sequencing is shown for example in Lapidus et al., U.S. Pat. No. 7,169,560, Quake et al. U.S. Pat. No. 6,818,395, Harris U.S. Pat. No. 7,282,337 and Braslaysky, et al., PNAS (USA), 100: 3960-3964 (2003), the contents of each of which are incorporated by reference herein.
  • next generation sequencing PCR or whole genome amplification can be performed on the nucleic acid in order to obtain a sufficient amount of nucleic acid for analysis.
  • no amplification is required because the method is capable of evaluating DNA sequences from unamplified DNA.
  • the sequence and/or genomic arrangement and/or genomic copy number of the nucleic acid from the test sample is compared to a standard reference derived from one or more individuals not known to suffer from a disease associated with exposure to inhaled carcinogens at the time their sample was taken. All differences between the sequence and/or genomic arrangement and/or genomic arrangement and/or copy number of the nucleic acid from the test sample and the standard reference are considered variants.
  • the DNA sequences derived from coding exons of genes included in the assay are enriched by bulk hybridization of randomly fragmented genomic DNA to specific RNA probes.
  • the same adapter sequences are attached to the ends of all fragments, allowing enrichment of all hybridization-captured fragments by PCR with one primer pair in one reaction. Regions that are less efficiently captured by hybridization are amplified by PCR with specific primers.
  • PCR with specific primers is may be used to amplify exons for which similar sequences (“pseudo exons”) exist elsewhere in the genome.
  • nucleotide A, G, T, or C
  • A, G, T, or C a fluorescently labeled dCTP
  • This nucleotide will only be incorporated into those growing complementary DNA strands that need a C as the next nucleotide.
  • an image of the flow cell is taken to determine which fragment was extended. DNA strands that have incorporated a C will emit light, while DNA strands that have not incorporated a C will appear dark. Chain termination is reversed to make the growing DNA strands extendible again, and the process is repeated for a total of 120 cycles.
  • the images are converted into strings of bases, commonly referred to as “reads,” which recapitulate the 3′ terminal 25 to 60 bases of each fragment.
  • the reads are then compared to the reference sequence for the DNA that was analyzed. Since any given string of 25 bases typically only occurs once in the human genome, most reads can be “aligned” to one specific place in the human genome. Finally, a consensus sequence of each genomic region may be built from the available reads and compared to the exact sequence of the reference at that position. Any differences between the consensus sequence and the reference are called as sequence variants.
  • certain molecules used in accordance with and/or provided by the invention comprise one or more detectable entities or moieties, i.e., such molecules are “labeled” with such entities or moieties.
  • Oregon Green Dyes e.g., Oregon Green 488, Oregon Green 500, Oregon Green 514., etc.
  • Texas Red Texas Red-X
  • SPECTRUM RED SPECTRUM GREEN
  • cyanine dyes e.g., CY-3, CY-5, CY-3.5, CY-5.5, etc.
  • ALEXA FLUOR dyes e.g., ALEXA FLUOR 350, ALEXA FLUOR 488, ALEXA FLUOR 532, ALEXA FLUOR 546, ALEXA FLUOR 568, ALEXA FLUOR 594, ALEXA FLUOR 633, ALEXA FLUOR 660, ALEXA FLUOR 680, etc.
  • BODIPY dyes e.g., BODIPY FL, BODIPY R6G, BODIPY R, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 5
  • a detectable moiety may include more than one chemical entity such as in fluorescent resonance energy transfer (FRET).
  • FRET fluorescent resonance energy transfer
  • the first fluorescent molecule absorbs light and transfers it through the resonance of excited electrons to the second fluorescent molecule (the “acceptor” fluor).
  • both the donor and acceptor dyes can be linked together and attached to the oligo primer. Methods to link donor and acceptor dyes to a nucleic acid have been described, for example, in U.S. Pat. No.
  • a detectable moiety is a radioactive isotope.
  • a molecule may be isotopically-labeled (i.e., may contain one or more atoms that have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature) or an isotope may be attached to the molecule.
  • Non-limiting examples of isotopes that can be incorporated into molecules include isotopes of hydrogen, carbon, fluorine, phosphorous, copper, gallium, yttrium, technetium, indium, iodine, rhenium, thallium, bismuth, astatine, samarium, and lutetium (i.e., 3H, 13C, 14C, 18F, 19F, 32P, 35S, 64Cu, 67Cu, 67Ga, 90Y, 99mTc, 111In, 125I, 123I, 129I, 131I, 135I, 186Re, 187Re, 201Tl, 212Bi, 213Bi, 211At, 153Sm, 177Lu).
  • kits for use in accordance with methods and compositions disclosed herein.
  • kits comprise one or more reagents detect the biomarker of interest.
  • Suitable reagents may include nucleic acid probes and/or antibodies or fragments thereof.
  • suitable reagents are provided in a form of an array such as a microarray or a mutation panel.
  • Kits may also contain instructions on how to determine if an individual has the disease and/or syndrome of interest, or is at risk of developing the disease and/or syndrome of interest.
  • the disclosure comprises methods to identify biomarkers for a syndrome or disease of interest (i.e., variants in nucleic acid sequence that are associated with a disease associated with exposure to inhaled carcinogens in a statistically significant manner).
  • the genes and/or genomic regions assayed for new markers may be selected based upon their importance in biochemical pathways that show genetic linkage and/or biological causation to the syndrome and/or disease of interest.
  • the genes and/or genomic regions assayed for markers may be selected based on genetic linkage to DNA regions that are genetically linked to the inheritance of a disease associated with exposure to an inhaled carcinogen in families.
  • the genes and/or genomic regions assayed for markers may be evaluated systematically to cover certain regions of chromosomes not yet evaluated.
  • a variant or a variant combination is reported or known to be transmitted exclusively or preferentially to individuals having the syndrome and/or disease of interest, it is considered to be at least potentially predisposing to the syndrome and/or disease of interest. Conversely, if a variant is found in both populations at a similar frequency, it is less likely to be associated with the development of the syndrome and/or disease of interest.
  • a variant or a variant combination is predicted to have an overall deleterious effect on a protein or gene expression (i.e., resulting in a nonsense mutation, a frameshift mutation, or a splice site mutation, or even a missense mutation), based on the predicted effect on the sequence and/or the structure of a protein or a nucleic acid, and if this variant or variant combination affects a gene or genes known to be associated with the syndrome and/or disease of interest, it is considered to be at least potentially predisposing to the syndrome and/or disease of interest.
  • the disclosure herein provides methods for diagnosing the presence or an increased risk of developing a disease associated with in a subject.
  • Such methods may include obtaining a nucleic acid from a sample of tissue or body fluid.
  • the method may further include sequencing the nucleic acid or determining the genomic arrangement or copy number of the nucleic acid to detect whether there is a variant or variants in the nucleic acid sequence or genomic arrangement or copy number.
  • the method may further include the steps of assessing the clinical significance of a variant or variants.
  • Such analysis may include an evaluation of the extent of association of the variant sequence in affected populations (i.e., subjects having the disease).
  • Such analysis may also include an analysis of the extent of the effect the mutation may have on gene expression and/or protein function.
  • the method may also include diagnosis the presence or an increased risk of developing a disease related to exposure to inhaled carcinogens based on the assessment.
  • EGFR expression levels are measured by fluorescent in situ hybridization (FISH) using 4-5 micron FFPE sections of tissue.
  • FISH fluorescent in situ hybridization
  • expresssion may be measured in serum, plasma, urine, bone marrow, blood, cerebrospinal fluid, FNA, or bone marrow.
  • Gene mutation analysis is performed using real-time PCR, single base extension and/or DNA sequencing. Gene mutation can be determined in, for examples, tissue, serum, plasma or urine.
  • Interleukin 8 (IL8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells.
  • the interleukin-8 protein is encoded by the CXCL8 gene.
  • IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms.
  • a 72 amino acid peptide is the major form secreted by macrophages IL-8, also known as neutrophil chemotactic factor, has two primary functions.
  • Plasminogen activator inhibitor-1 also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis. PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), activators of plasminogen and fibrinolysis. It is a serine protease inhibitor (serpin) protein (SERPINE1).
  • the PAI-1 gene is SERPINE1, located on chromosome 7 (7q21.3-q22). There is a common polymorphism known as 4G/5G in the promoter region. The 5G allele is slightly less transcriptionally active than the 4G.
  • STAT3 Signal Transducer and Activator of Transcription 3
  • IL-6 's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10.
  • IL-6 is an important mediator of fever and of the acute phase response. It is capable of crossing the blood-brain barrier, initiating synthesis of PGE2 in the hypothalamus, and changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature.
  • IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs), and is also considered a myokine (a cytokine produced from muscle), which is elevated in response to muscle contraction
  • PAMPs pathogen-associated molecular patterns
  • VEGF Vascular endothelial growth factor
  • VPF vascular permeability factor
  • VEGF has potent angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells.
  • VEGF is thought to play an important role in several physiologic processes, including wound healing, ovulation, menstruation, maintenance of blood pressure, and pregnancy.
  • VEGF has also been associated with a number of pathologic processes that involve angiogenesis, including arthritis, psoriasis, macular degeneration, and diabetic retinopathy.
  • tumor expression of proangiogenic factors, including VEGF has been associated with advanced tumor progression in a number of human cancers.
  • VEGF can be measured in serum using enzyme immunoassay (EIA).
  • CCL2 The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2.
  • CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection. Administration of anti-CCL2 antibodies in a model of glomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment. Hypomethylation of CpG sites within the CCL2 promoter region is affected by high levels of blood glucose and TG, which increase CCL2 levels in the blood serum. The later plays an important role in the vascular complications of type 2 diabetes.
  • Phosphatidylinositol-4,5,-bisphosphate 3-kinase Catalytic Subunit Alpha PIK3CA

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