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WO2019208739A1 - Procédé d'évaluation de l'appartenance au groupe ayant un bon pronostic après un traitement contre le cancer et procédé d'évaluation de l'appartenance au groupe à risque de développer un cancer à un jeune âge - Google Patents

Procédé d'évaluation de l'appartenance au groupe ayant un bon pronostic après un traitement contre le cancer et procédé d'évaluation de l'appartenance au groupe à risque de développer un cancer à un jeune âge Download PDF

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Publication number
WO2019208739A1
WO2019208739A1 PCT/JP2019/017807 JP2019017807W WO2019208739A1 WO 2019208739 A1 WO2019208739 A1 WO 2019208739A1 JP 2019017807 W JP2019017807 W JP 2019017807W WO 2019208739 A1 WO2019208739 A1 WO 2019208739A1
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Prior art keywords
cancer
group
subject
polymorphism
gene
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PCT/JP2019/017807
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English (en)
Japanese (ja)
Inventor
哲治 岡本
亮治 谷
浩一郎 徳丸
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.)
Nihon Kefir Co ltd
Hiroshima University NUC
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Nihon Kefir Co ltd
Hiroshima University NUC
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Priority to JP2020515588A priority Critical patent/JP7399399B2/ja
Publication of WO2019208739A1 publication Critical patent/WO2019208739A1/fr
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • 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
    • C12Q1/6869—Methods for sequencing

Definitions

  • the present invention relates to a method for determining whether a cancer belongs to a good prognosis group after cancer treatment and a method for determining whether a subject belongs to a juvenile cancer risk group.
  • the frequency of testing should be planned more effectively. It is desirable from the viewpoint of QOL and medical resource allocation.
  • the MICA gene (MHC class I chain-related gene A) product is a ligand for activated NK cell receptor NKG2D such as NK cells and ⁇ T cells, and activation signals mediated by the receptor are infection immunity and autoimmunity against viruses. It is said that it contributes to various immune responses such as diseases. For this reason, various therapeutic agents have been developed for the MICA gene or gene product thereof as a target for the action of the therapeutic agent (for example, Patent Document 1).
  • Non-patent Document 1 The presence of genetic polymorphism is known for the MICA gene, and it has been reported that there are five types of genetic polymorphism in exon5 encoding a transmembrane region (Non-patent Document 1).
  • an object of the present invention is to provide a novel method for determining whether or not a subject has a good prognosis after cancer treatment, and to provide a novel method for determining whether or not a subject belongs to a juvenile cancer risk group. is there.
  • the present inventor has been engaged in the clinical treatment of cancer and has been diligently researching the treatment results for many years. As a result, a human having A5.1 type as the MICA gene polymorphism has a young age of onset of oral cancer. In addition, the present inventors have found that the prognosis of treatment of oral cancer is good and reached the present invention.
  • the present invention includes the following (1) and below.
  • (1) A method of determining whether a subject belongs to a good prognosis group after cancer treatment by identifying a genetic polymorphism in exon 5 of the subject's MICA gene.
  • (2) The determination method according to (1), wherein the gene polymorphism in exon 5 of the MICA gene of the test subject is determined to belong to a good prognosis group when having A5.1 type as a homozygote.
  • the determination method according to any one of (1) to (2), wherein the good prognosis group is a group having a survival rate of 95% or more after 5 years.
  • (4) The determination method according to any one of (1) to (3), wherein the subject is a cancer patient or a healthy person.
  • the determination method according to any one of (1) to (4), wherein the cancer is human oral cancer.
  • (6) A method for determining whether a subject belongs to a juvenile cancer risk group by identifying a genetic polymorphism in exon 5 of the subject's MICA gene.
  • the subject has a homozygote of A5.1 type or a heterozygote of A5.1 type and A5 type as a genetic polymorphism in exon 5 of the MICA gene of the subject, the risk of developing juvenile cancer (6) The determination method according to (6).
  • 10 The determination method according to any one of (6) to (9), wherein the cancer is human oral cancer.
  • a prediction method, an estimation method, an evaluation method, a detection method, a determination method, an analysis method, an inspection method, a diagnosis method, a classification method, a classification method, and a selection method including the above-described determination method.
  • a prediction method, an estimation method, an evaluation method, a detection method, a determination method, an analysis method, an inspection method, a diagnosis method, a classification method, a classification method, and a selection method including the above-described determination method.
  • the step of identifying a genetic polymorphism in exon 5 of the subject's MICA gene can be performed using a sample collected from the subject, and the sample containing the gene from the subject prior to the step Can be performed.
  • the step of identifying a gene polymorphism in exon 5 of the subject's MICA gene can be performed by a known polymorphism identifying means, for example, by a polymorphism identifying means using a PCR method.
  • a step of performing PCR amplification of a gene in exon 5 of a subject's MICA gene using a primer at an appropriate position containing exon 5 and then identifying a polymorphism by using a PCR product based on a difference in the number of bases can be implemented.
  • the present invention it can be determined whether the cancer belongs to a good prognosis group after cancer treatment. Moreover, according to this invention, it can be determined whether a test subject belongs to the juvenile cancer onset risk group. As a result, it is possible to plan more effectively how often examinations should be performed, etc., which brings great benefits to individuals and society from the viewpoint of QOL and medical resource allocation.
  • FIG. 1 is an explanatory diagram of the MICA gene product.
  • FIG. 2 is an explanatory diagram showing five types of gene polymorphisms present in exon5 encoding the transmembrane region of the MICA gene.
  • FIG. 3 is an explanatory diagram of a polymorphism analysis chromatogram obtained by separating each PCR product with a capillary column based on the difference in the number of bases.
  • FIG. 4 shows the survival curve of oral cancer patients by Kaplan-Meier method with A5.1 / 5.1 homozygote and all other Genotype polymorphisms (non-A5.1 / 5.1). It is the graph shown by contrast.
  • Method to determine if cancer belongs to good prognosis after cancer treatment it is possible to determine whether a subject belongs to a good prognosis group after cancer treatment by identifying a genetic polymorphism in exon 5 of the subject's MICA gene.
  • the gene polymorphism in exon 5 of the subject's MICA gene belongs to a good prognosis group when it has A5.1 type homozygote.
  • the cancer is not particularly limited, but preferably can be suitably determined for human oral cancer.
  • human oral cancer include tongue cancer, gingival cancer, oral cavity cancer, buccal mucosa cancer, maxillary sinus cancer, oral pharyngeal cancer, and salivary gland cancer.
  • cancers of organs adjacent to human oral cancer include nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, and esophageal cancer.
  • the good prognosis group refers to a group having a good prognosis using the survival rate as an index, and can be expressed by, for example, a 5-year survival rate, a 10-year survival rate, or a 20-year survival rate.
  • a group in which the 5-year survival rate is 90% or more, 95% or more, or 99% or more can be mentioned, for example, the 10-year survival rate is 90% or more, 95% or more, 99%.
  • a group having a 20-year survival rate of 90% or more, 95% or more, or 99% or more can be given. As shown in the examples of the present invention, in a particularly preferred case, the 20-year survival rate was 100%.
  • the subject who determines whether or not it belongs to the good prognosis group after cancer treatment may be a cancer patient or a healthy person. If it is a cancer patient, the prognosis after cancer treatment can be determined, and if it is a healthy person, the prognosis after cancer treatment when cancer develops can be determined.
  • Method to determine if it belongs to juvenile cancer risk group According to the present invention, by identifying a genetic polymorphism in exon 5 of a subject's MICA gene, it can be determined whether the subject belongs to a juvenile cancer risk group.
  • the subject when the subject has the A5.1 type as a genetic polymorphism in exon 5 of the MICA gene, it can be determined that it belongs to the juvenile cancer risk group.
  • the polymorphism in exon 5 of the subject's MICA gene has a homozygote of A5.1 type or a heterozygote of A5.1 type and A5 type. It can be determined that it belongs to the juvenile cancer onset risk group.
  • the cancer is not particularly limited, but preferably can be suitably determined for human oral cancer.
  • human oral cancer include tongue cancer, gingival cancer, oral cavity cancer, buccal mucosa cancer, maxillary sinus cancer, oral pharyngeal cancer, and salivary gland cancer.
  • cancers of organs adjacent to human oral cancer include nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, and esophageal cancer.
  • the juvenile cancer risk group refers to a group that has a high risk of developing cancer at a young age, and specifically refers to a group that has a high risk of cancer development at the age of 20 to 39 years.
  • the 20-39-year-old almost overlaps with the AYA (Adolescents and Young Adult) (adolescent and young adult) generation (15 years old and under 40 years old) advocated by the Ministry of Health, Labor and Welfare. Patients who have developed cancer in this age are particularly expected to return to society after cancer treatment, so predicting the onset of cancer in this age and starting appropriate treatment early is important. Especially significant.
  • the risk of developing cancer at 20-39 years is higher than the proportion of cancer onset at 20-39 years compared to other age groups such as 40-59 years, 60-79 years, 80-100 years And say significantly more.
  • MICA gene polymorphism As described in the examples described later, it has been reported that the MICA gene has five types of gene polymorphisms in exon5 encoding a transmembrane region. As described above, among these polymorphisms, in the present invention, the determination is made by identifying the A5.1 type.
  • a known technique can be used, for example, the means disclosed in the Examples can be used.
  • genomic DNA obtained from a cell is PCR amplified using a primer at an appropriate position including exon 5, and the obtained PCR product is applied to a capillary column with CEQ8000, and the difference in the number of bases is determined. Polymorph identification can be performed to identify the subject's Genotype.
  • MICA gene polymorphism MHC class I chain-related gene A (MICA) is a ligand of activated NK cell receptor NKG2D such as NK cells and ⁇ T cells, and activation signals mediated by the receptor are infectious immunity against viruses, tumor immunity, self It is said that it contributes to various immune responses such as immune diseases.
  • An explanatory diagram of this MICA gene product is shown in FIG.
  • the MICA gene has been reported to have 5 types of gene polymorphisms in exon5 encoding a transmembrane region. An explanatory diagram of these five gene polymorphisms is shown in FIG. As shown in FIG.
  • the base sequence in the polymorphisms A4, A5, A6, and A9, is [GCT] [GCT] in exon 5, followed by this last T (base 951 of exon 5). Furthermore, the base sequence continues with [GCT] [GCT].
  • the base sequence in the A5.1 polymorphism, is [GCT] [GCT] in exon 5, followed by this last T (base 951 of exon 5), and then G is inserted. The base sequence continues with [GCT] [GCT].
  • the codon frame is shifted, and the encoded amino acid sequence is different from other polymorphisms.
  • Genomic DNA extraction method using QIA amp (registered trademark) DNA Blood midi kit (QIAGEN) was performed according to the attached protocol.
  • the extracted DNA was quantified using Nano Drop (Nano Drop Technologies, Inc., USA).
  • genomic DNA was extracted from the OSCC tissue piece using QIA amp (registered trademark) DNA mini kit (QIAGEN) according to the attached protocol.
  • QIA amp registered trademark DNA mini kit
  • the extracted DNA was quantified using Nano Drop (Nano Drop Technologies, Inc., USA).
  • PCR Polymerase Chain Reaction
  • FIG. 3 shows, as an explanatory diagram, a polymorphism analysis chromatogram obtained by separating each PCR product with a capillary column using CEQ8000 based on the difference in the number of bases.
  • the obtained PCR product was used to purify the PCR product using a QlAquick (registered trademark) PCR Purification Kit (Qiagen).
  • QlAquick registered trademark
  • Qiagen PCR Purification Kit
  • Table 1-1 summarizes the results of MICA polymorphism comparison (by Phenotype) between healthy individuals and oral cancer patients by age group.
  • Table 1-2 shows the results of chi-square test (P value) corresponding to Table 1-1.
  • P value chi-square test
  • Table 1-1 summarizes the results of MICA polymorphism comparison (by Phenotype) between healthy individuals and oral cancer patients by age group.
  • Table 1-2 shows the results of chi-square test (P value) corresponding to Table 1-1.
  • P value chi-square test
  • Table 2-1 summarizes the results of MICA polymorphism comparison (by allele) between healthy individuals and oral cancer patients by age group.
  • Table 2-2 shows the results of chi-square test (P value) corresponding to Table 2-1.
  • P value chi-square test
  • Table 3 summarizes the results of MICA polymorphism comparison (by Genotype) between healthy individuals and oral cancer patients by age group. Table 3 further shows the results of chi-square test (P value).
  • * (asterisk) was attached
  • In comparison between healthy individuals and oral cancer patients there was a significant difference especially in the A5.1 / 5.1 Genotype group of 20-39 years old.
  • In comparison between healthy individuals and oral cancer patients there was a significant difference especially in the group of A5.1 / 5 Genotype 20-39 years old. That is, it was found that both Genotypes A5.1 / 5.1 and A5.1 / 5 are in the juvenile cancer risk group.
  • Table 4 summarizes the results of MICA polymorphism comparison (by Genotype) of oral cancer patients by age group. Table 4 further shows the results of chi-square test (P value). In Table 4, those having a significant difference are marked with * (asterisk). There was a significant difference between the A5.1 / 5.1 Genotype group and the A5.1 / 5 Genotype group in comparisons between 20-39 years old and other age-specific oral cancer patients. That is, it was found that Genotype of A5.1 / 5.1 in the 20-39 years of age has a higher risk of onset compared to other age groups of cancer patients.
  • Table 6 summarizes the results of treatment details for the A5.1 / 5.1 homozygote and all other Genotype polymorphisms (non-A5.1 / 5.1).
  • the abbreviations indicate CRT: chemotherapy + radiotherapy, C: chemotherapy, RT: radiation therapy, respectively.
  • C chemotherapy + radiotherapy
  • C chemotherapy
  • RT radiation therapy
  • the present invention provides a method for determining whether or not a subject has a good prognosis after cancer treatment and a method for determining whether or not a subject belongs to a juvenile cancer risk group.
  • the present invention is an industrially useful invention.

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Abstract

L'invention concerne : un procédé permettant de déterminer si un sujet est un membre d'un groupe ayant un bon pronostic après un traitement contre le cancer par l'identification du polymorphisme génétique de l'exon 5 du gène MICA du sujet ; et un procédé permettant d'évaluer si un sujet fait partie d'un groupe à risque de développer un cancer à un jeune âge par l'identification du polymorphisme génétique de l'exon 5 du gène MICA du sujet.
PCT/JP2019/017807 2018-04-25 2019-04-25 Procédé d'évaluation de l'appartenance au groupe ayant un bon pronostic après un traitement contre le cancer et procédé d'évaluation de l'appartenance au groupe à risque de développer un cancer à un jeune âge Ceased WO2019208739A1 (fr)

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JP2020515588A JP7399399B2 (ja) 2018-04-25 2019-04-25 癌治療後に予後良好群に属するかを判定する方法、及び若年性癌発症リスク群に属するかを判定する方法

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053018A2 (fr) * 2001-01-08 2002-07-11 Genomics Collaborative, Inc. Procede d'identification et de gestion de l'augmentation des risques de cancer du sein associes a des polymorphismes des genes mhc
US20150218635A1 (en) * 2011-12-14 2015-08-06 Fundación Pública Andaluza Progreso Y Salud Method for obtaining data that can be used for the diagnosis and prognosis of neurosensory hypoacusis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053018A2 (fr) * 2001-01-08 2002-07-11 Genomics Collaborative, Inc. Procede d'identification et de gestion de l'augmentation des risques de cancer du sein associes a des polymorphismes des genes mhc
US20150218635A1 (en) * 2011-12-14 2015-08-06 Fundación Pública Andaluza Progreso Y Salud Method for obtaining data that can be used for the diagnosis and prognosis of neurosensory hypoacusis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN, DAN ET AL.: "A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population", CANCER MEDICINE, vol. 3, no. 1, 2014, pages 190 - 198 *

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JPWO2019208739A1 (ja) 2021-04-30

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