がんの新規ゲノム異常の探索と多項目遺伝情報によるがんの個性診断法の開発

• Project/Area Number: 12217045
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 稲澤 譲治 東京医科歯科大学, 難治疾患研究所, 教授 (30193551)
• Co-Investigator(Kenkyū-buntansha): 井本 逸勢 東京医科歯科大学, 難治疾患研究所, 助教授 (30258610) ; 安居 幸一郎 東京医科歯科大学, 難治疾患研究所, 助手 (30323695)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥62,000,000 (Direct Cost: ¥62,000,000); Fiscal Year 2004: ¥13,700,000 (Direct Cost: ¥13,700,000); Fiscal Year 2003: ¥12,300,000 (Direct Cost: ¥12,300,000); Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 2001: ¥14,000,000 (Direct Cost: ¥14,000,000); Fiscal Year 2000: ¥12,000,000 (Direct Cost: ¥12,000,000)
• Keywords: がん / 微細ゲノム構造異常 / がん遺伝子 / 遺伝子増幅 / がん抑制遺伝子 / CGHアレイ / 網羅的 / メチル化 / 癌 / 染色体 / ゲノム / 遺伝子 / 個性診断 / マイクロアレイ / CGH / 癌関連遺伝子 / アポトーシスインヒビター / 腫瘍 / ゲノム異常 / 癌関連遺伝 / 遺伝子診断 / マイクロアイレ

Research Abstract

ポストシーケンスの癌研究において、基礎研究で得られた成果を基盤に実地臨床への応用が可能となる新しい診断、治療、予防法の開発に多大な期待が寄せられている.今回の研究では、各種の癌細胞において、網羅的ゲノム一次構造異常解析、エピジェネチック遺伝子制御機構、体系的遺伝子発現などの統合的な癌ゲノム解析を推進し、癌の個別化医療の実現に資する成果を目的に研究を行った.その結果、(1)種々の病型において900例以上の癌のCGH解析を行い、この結果を"CGH databsase"として公開した(http://www.cghtmd.jp/cghdatabase/index.html).(2)総数7099個のBACクローンを配置した5種類の高精度ゲノムDNAアレイを作製した.(3)CGHアレイにより検出した新規の増幅、ホモ欠失領域より新しい癌関連遺伝子候補を見出した.(4)ゲノムDNAアレイをプラットフォームにメチル化DNAの探索法(BAC array-based MAC ; BAMCA法)やクロマチン免疫沈降法(ChIP-on-chip法)の応用法を確立した.(5)小児急性リンパ性白血病のt(1;19)転座より新規の切断点融合遺伝子MEF2D/DAZAP1を同定した.
さらに、具体的な固形腫瘍の癌関連遺伝子探索の成果は以下である.食道扁平上皮癌(ESC)細胞株の癌抑制遺伝子LRP1B遺伝子(2q22.1)を同定した(Cancer Res. 2004).肺非小細胞癌(SCLC)の5p13増幅の標的としてSKP2を特定し、その機能亢進が遊走能、浸潤能に関与することを明らかにした(Am J Pathol. 2004).さらに、NSCLCで検出した新規ホモ欠失領域から、肺癌抑制遺伝子DBC1を同定した(Hum Molec Genet. in press).胃癌細胞株32例のCGHアレイ解析を行った.新規増幅をCDK6(7q21.2)に検出した(Cancer Sci. 2005).さらに、新規ホモ欠失領域を検出し標的癌抑制遺伝子候補のMCG22(仮称)を同定した(投稿中).その他に、多発性骨髄腫の1q21増幅の標的PDZK1と薬剤耐性獲得(Am J Pathol. 2004)、各種抗癌剤の薬剤耐性獲得メカニズムと特定ゲノム構造異常の解析(Cancer Res. 2004)などの成果を得た.

Research Products

• [Journal Article] Alteration in copy numbers of genes as a mechanism for acquired drug resistance (2004)
  • Author(s): Yasui K, Inazawa J et al.
  • Journal Title: Cancer Research 64 Pages: 1403-1410
• [Journal Article] Frequent silencing of low density lipoprotein receptor-related protein 1B(LRP1B) expression by genetic and epigenetic mechanisms in esophageal squamous-cell carcinoma (2004)
  • Author(s): Sonoda I, Inazawa J et al.
  • Journal Title: Cancer Research 64 Pages: 741-747
• [Journal Article] Skp2 Overexpression is a p27Kip1-independent poor prognosticator in patients with biliary tract cancers (2004)
  • Author(s): Sanada T, Inazawa J et al.
  • Journal Title: Cancer Science 95 Pages: 969-976
• [Journal Article] Comparative genomic hybridization (CGH) arrays pave the way for identification of novel cancer-related genes (2004)
  • Author(s): Inazawa J et al.
  • Journal Title: Cancer Science 95 Pages: 559-563
• [Journal Article] Amplification and Overexpression of SKP2 Are Associated with Metastasis of Non-Small-Cell Lung Cancers to Lymph Nodes (2004)
  • Author(s): Yokoi S, Inazawa J et al.
  • Journal Title: Am J Pathol 165 Pages: 175-180
• [Journal Article] Overexpression of PDZK1 within the 1q12-q22 Amplicon Is Likely To Be Associated with Drug-Resistance Phenotype in Multiple Myeloma. (2004)
  • Author(s): Inoue J, Inazawa J et al.
  • Journal Title: Am J Pathol 165 Pages: 71-81
• [Book] 学術月報 (2004)
  • Author(s): 稲澤 譲治
  • Total Pages: 88
  • Publisher: 独立行政法人日本学術振興会
• [Patent(Industrial Property Rights)] 薬剤耐性を獲得した癌細胞の検出方法 (2004)
  • Inventor(s): 稲澤 譲治, 安居 幸一郎
  • Filing Date: 2004-02-04
• [Publications] Yasui K, Inazawa J et al.: "Alteration in Copy-Numbers of Genes as a Mechanism for Acquired Drug Resistance"Cancer Research. 64. 1403-1410 (2004)
• [Publications] Hirasawa A, Inazawa J et al.: "Relationship between Prognostic Factors and the Biological Mechanisms Accounting for Genetic Instability in Endometrial Adenocarcinoma of the Uterus"Clinical Cancer Research. 15. 5675-5682 (2003)
• [Publications] Okamoto H, Inazawa J et al.: "PTK2 and EIF3S3 Genes May be Amplification Targets at 8q23-q24 and Are Associated with Large Hepatocellular Carcin"Hepatology. 38. 1242-1249 (2003)
• [Publications] Imoto I, Inazawa J et al.: "Identification of ZASC1 Encoding a Kruppel-like Zinc Finger Protein as a Novel Target for 3q26 Amplification in Esophageal Squamous Cell Carcinomas"Cancer Research. 63. 5691-5696 (2003)
• [Publications] Yokoi S, Inazawa J et al.: "TERC Identified as a probable target within the 3q26 amplicon that is detected frequently in non-small cell lung cancers"Clinical Cancer Research. 15. 4705-1713 (2003)
• [Publications] Hirasawa A, Inazawa J et al.: "Association of 17q21-q24 Gain in Ovarian Clear Cell Adenocarcinomas with Poor Prognosis and Identification of PPM1D and APPBP2 as Likely Amplification Targets"Clinical Cancer Research. 9. 1995-2004 (2003)
• [Publications] 稲澤譲治: "生命科学"東京化学同人. 228 (2004)
• [Publications] Imoto I, Tsuda H, Inazawa J, et al.: "Expression of cIAP1, a target for 11q22 amplification, Correlates with Resistance of Cervical Cancers to Radiotherapy"Cancer Research. 62・17. 4860-4866 (2002)
• [Publications] Saito-Ohara F, Imoto I, Inazawa J, et al.: "PPM1D is a potential Target for 17q Gain in Neuroblastoma"Cancer Research. (印刷中). (2003)
• [Publications] Yokoi S, Yasui K, Inazawa J, et al.: "A novel target gene, SKP2, within the amplicon that is frequently detected in small cell lung cancers"American Journal of Pathology. 161・1. 207-216 (2002)
• [Publications] Saito-Ohara F, Fukuda Y, Inazawa J, et al.: "The Xq22 inversion breakpoint interrupted a novel Ras-like GTPase gene in a DMD patient with profound mental retardation"American Journal of Human Genetics. 71・3. 637-645 (2002)
• [Publications] Okamoto R, Inazawa J, et al.: "Damaged epithelia regenerated by bone marrow #150 ; derived cells in the human gastrointestinal tract"Nature Medicine. 8・9. 1011-1017 (2002)
• [Publications] Li QL, Ito K, Inazawa J, et al.: "Causal relationship between the loss of RUNX3 expression and gastric cancer"Cell. 109・1. 113-124 (2002)
• [Publications] Nakakuki K., et al.: "Novel targets for the 18p11.3 amplification frequently observed in esophageal squamous cell carcinomas"Carcinogenesis. 23・1. 19-24 (2002)
• [Publications] Imoto I., et al.: "Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas"Cancer Res.. 61・18. 6629-6634 (2001)
• [Publications] Yasui K., et al.: "Identification of target genes within an amplicon at 14q12-q13 in esophageal squamous cell carcinoma"Gene Chromosom Cancer. 32・2. 112-118 (2001)
• [Publications] Imoto I., et al.: "Identification and characterization of human PKNOX2, a novel homeobox-containing gene"Biochem.Biophys.Res.Commun. 287・1. 270-276 (2001)
• [Publications] Imoto I., et al.: "SNOis a probable target for gene amplification at 3q26 in squamous-cell carcinomas o the esophagus"Biochem.Biophys.Res.Commun. 286・3. 559-565 (2001)
• [Publications] Watanabe T., et al.: "Human arylhydrocarbon receptor repressor (AHRR) gene : genomic structure and analysis of polymorphism in endometriosis"J.Hum.Genet. 46・6. 342-346 (2001)
• [Publications] Yang Z-Q,Inazawa J. et al.: "A novel amplicon haboring NFIB proximal to GASC1 at 9p23-24 in squamous cell carcinoma of the esophagus."Jpn J Cancer Res. (in press). (2001)
• [Publications] Watanabe T,\ Inazawa J. et al.: "A Novel Amplification at 17q21-23 in Ovarian Cancer Cell Lines Detected by Comparative Genomic Hybridization."Gynecol Oncol. (in press). (2001)
• [Publications] Pimkhaokham A,Inazawa J. et al.: "Nonrandom Chromosomal Imbalances in Esophageal Squamous Cell Carcinoma Cell Lines : Possible Involvement of the ATF3 and CENPF Genes in the 1q32 Amplicon."Jpn J Cancer Res. 91. 1126-1133 (2000)
• [Publications] Fukuda Y,Inazawa J. et al: "CD44 is a potential target of amplification within the 11p13 amplicon detected in gastric-cancer cell lines."Genes Chromosomes Cancer. 29. 315-324 (2000)
• [Publications] Yang Z-Q,Inazawa J. et al.: "Identification of a Novel Gene, GASC1, within an Amplicon at 9p23-24 Frequently Detected in Esophageal Cancer Cell Lines."Cancer Res. 60. 4735-4739 (2000)
• [Publications] Yang Z-Q,Inazawa J. et al.: "Molecular cytogenetic analysis of 17 renal-cancer cell lines : increased copy number at 5q31-33 in cell lines from nonpapillary carcinomnas."Jpn J Cancer Res. 91. 156-163 (2000)
• [Publications] 稲澤譲治: "新女性医学大系第28巻・遺伝の基礎と臨床"中山書店. 461 (2000)