遺伝子不安定性癌における標的遺伝子変異に対する免疫応答の分子疫学的検索

• Project/Area Number: 13220017
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Sapporo Medical University
• Principal Investigator: 山本 博幸 札幌医科大学, 医学部, 助手 (40332910)
• Project Period (FY): 2001 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥31,300,000 (Direct Cost: ¥31,300,000); Fiscal Year 2004: ¥7,900,000 (Direct Cost: ¥7,900,000); Fiscal Year 2003: ¥7,400,000 (Direct Cost: ¥7,400,000); Fiscal Year 2002: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 2001: ¥8,000,000 (Direct Cost: ¥8,000,000)
• Keywords: マイクロサテライト不安定性 / 標的遺伝子 / フレームシフト変異 / aberrant oligopeptide / 免疫応答 / MRE11遺伝子 / BRAF遺伝子 / 民族間比較 / HLA遺伝子 / MMP-3遺伝子 / SEC63遺伝子 / β2マイクログロブリン遺伝子

Research Abstract

マイクロサテライト不安定性(MSI)陽性がんにおいてフレームシフト変異により産生される変異蛋白とそれに対する宿主側の免疫応答とがん進展、がん細胞側の免疫エスケープ機序、シグナル伝達系の異常、予後との関連を日本および諸外国の研究室から提供された試料について、アレイ解析技術も用いて系統的に解析した。網羅的に明らかにしたフレームシフト変異の新規標的遺伝子の変異の頻度に各民族間において有意な差を認めなかった。宿主側の免疫応答の亢進およびがん細胞側の免疫エスケープ機序の詳細を明らかにした。MRE11遺伝子イントロン領域の繰り返し配列(T)11における変異が高頻度におき、スプライシング異常から、正常型MRE11の発現が低下し、染色体不安定性と関連していることを明らかにした。シグナル伝達系の異常に関し、ヒト多段階発がん機構の中心をなすRAS/RAF/MAPK pathwayとMSIについて系統的に検索し、MSI陽性大腸がんにおいて、散発性ではBRAF遺伝子が、遺伝性非ポリポーシス大腸がん(HNPCC)では、K-ras遺伝子が変異の主要なターゲットとなっていることを明らかにした。また、BRAF V599E遺伝子変異検索はHNPCCの除外診断に有用であることを明らかにした。さらに、BRAF V599E遺伝子変異が宿主のT細胞反応を惹起することを明らかにした。また、散発性MSI陰性大腸がん、散発性MSI陽性大腸がん、HNPCCそれぞれに、K-ras遺伝子の変異型に特徴があることを見出した。

Research Products

• [Journal Article] BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC patients with functional MLH1 and MSH2 genes (2005)
  • Author(s): Enric Domingo
  • Journal Title: Oncogene 24(in press)
• [Journal Article] Activated BRAY targets proximal colon tumors with mismatch repair deficiency and hMLH1 inactivation (2004)
  • Author(s): Enric Domingo
  • Journal Title: Genes Chromosomes Cancer 39 Pages: 138-142
• [Journal Article] Braf screening as a low-cost effective strategy for simplifying HNPCC genetic testing (2004)
  • Author(s): Enric Domingo
  • Journal Title: J Med Genet 41 Pages: 663-667
• [Journal Article] Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLHl methylation status (2004)
  • Author(s): Carla Oliveira
  • Journal Title: Hum Mol Genet 13 Pages: 2303-2311
• [Journal Article] Expression of ets-related transcriptional factor E1AF is associate with tumor progression and overexpression of matrilysin in human gastric cancer (2004)
  • Author(s): Hiroyuki Yamamoto
  • Journal Title: Carcinogenesis 25 Pages: 325-332
• [Journal Article] Interplay of IGF-II, IGF-I, IGF-I receptor, COX-2, and MMP-7 plays key roles in the early stage of colorectal carcinogenesis (2004)
  • Author(s): Katsuhiko Nosho
  • Journal Title: Clin Cancer Res 10 Pages: 7950-7957
• [Publications] Carla Oliveira: "Activated BRAF mutations characterize colon but not gastric cancer with mismatch repair"Oncogene. 22. 9192-9196 (2003)
• [Publications] Enric Domingo: "Activated BRAF targets proximal colon tumors with mismatch repair deficiency and hMLH1 inactivation"Genes Chromosomes Cancer. 39. 138-142 (2004)
• [Publications] Hiroyuki Yamamoto: "Association of trypsin expression with tumor progression and matrilysir expression in human colorectal cancer"Journal of Pathology. 199. 176-184 (2003)
• [Publications] Yongfen Min: "Genetic blockade of the insulin-like growth factor-I receptor : a promising strategy for human pancreatic cancer"Cancer Research. 63. 6432-6441 (2003)
• [Publications] Shina Horiuchi: "Association of Ets-related transcriptional factor E1AF expression with tumor progression and overexpression of MMP-1 and matrilysin in human colorectal cancer"Journal of Pathology. 200. 568-576 (2003)
• [Publications] Hiroyuki Yamamoto: "Expression of ets-related transcriptional factor E1AF is associated with tumor progression and overexpression of matrilysin in human gastric cancer"Carcinogenesis. 25. 325-332 (2004)
• [Publications] Hiroyuki Yamamoto: "Gastrointestinal cancer of the microsatellite mutator phenotype pathway"Journal of Gastroenterology. 37. 153-163 (2002)
• [Publications] Hiroyuki Yamamoto: "Microsatellite instability and gastrointestinal cancer"Gastrointestinal Function. 2. 121-129 (2002)
• [Publications] Hiroyuki Takahashi: "Mucin Phenotype and microsatellite instability in multiple early gastric cancers"International Journal of Cancer. 100. 419-424 (2002)
• [Publications] Hiroyuki Yamamoto: "Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability"Genes, Chromosomes and Cancer. 33. 322-325 (2002)
• [Publications] Hiroyuki Yamamoto: "Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability"Genes,Chromosomes and Cancer. 33. 322-325 (2002)
• [Publications] Anna Menoyo: "Somatic mutations in the DNA damage-response genes ATR and chk1 in sporadic stomach tumors with microsatellite instability"Cancer Research. 61. 7727-7730 (2001)
• [Publications] Naoki Ohmiya: "Germline and somatic mutations in MSH6 and MSH3 in gastrointestinal cancers of the microsatellite mutator phenotype"Gene. 272. 301-313 (2001)
• [Publications] Hiroshi Fukushima: "Frequent alterations of the β-catenin and TCF-4 genes but not of the APC gene in colon cancers with high-frequency microsatellite instability"Journal of Experimental and Clinical Cancer Research. 20. 553-559 (2001)
• [Publications] Hiroyuki Yamamoto: "Gastrointestinal cancer of the microsatellite mutator phenotype pathway"Journal of Gastroenterology. (印刷中). (2002)