Cancer genomics analysis and biomarker discovery under therapeutic modification

• Project Area: Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention
• Project/Area Number: 22134003
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Tokyo Medical and Dental University (2012-2014); The University of Tokyo (2010-2011)
• Principal Investigator: ISHIKAWA Shumpei 東京医科歯科大学, 難治疾患研究所, 教授 (50418638)
• Co-Investigator(Kenkyū-buntansha): MAEDA Daichi 秋田大学, 大学院医学系研究科, 准教授 (30585500)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥103,740,000 (Direct Cost: ¥79,800,000、Indirect Cost: ¥23,940,000); Fiscal Year 2014: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000); Fiscal Year 2012: ¥21,320,000 (Direct Cost: ¥16,400,000、Indirect Cost: ¥4,920,000); Fiscal Year 2011: ¥21,060,000 (Direct Cost: ¥16,200,000、Indirect Cost: ¥4,860,000); Fiscal Year 2010: ¥21,710,000 (Direct Cost: ¥16,700,000、Indirect Cost: ¥5,010,000)
• Keywords: ゲノム / がん / 治療標的 / 薬剤応答性 / シグナル伝達 / 薬剤反応性 / バイオマーカー / ゲノミクス / 治療薬

Outline of Final Research Achievements

We tried to identify the therapeutic targets and biomarkers of uncharacterized chemical compound by genomics analysis of the resistant sub-clone cells and functional genomics screening. We also established the antigen receptor repertoire analysis technology of tumor infiltrating lymphocytes for biomarker discovery of the cancer immunotherapy. For diffuse-type gastric cancer, where the valid molecular target is absent, we performed the whole exome sequencing and have identified RHOA driver gene mutations as potential therapeutic targets.

Research Products

• [Journal Article] Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. (2014)
  • Author(s): Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, Yamamoto S, Tatsuno K, Katoh H, Watanabe Y, Ichimura T, Ushiku T, Funahashi S, Tateishi K, Wada I, Shimizu N, Nomura S, Koike K, Seto Y, Fukayama M, Aburatani H, Ishikawa S
  • Journal Title: Nat Genet. Volume: 46(6) Issue: 6 Pages: 583-7
  • DOI: 10.1038/ng.2984
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. (2014)
  • Author(s): Tanaka M, Suzuki HI, Shibahara J, Kunita A, Isagawa T, Yoshimi A, Kurokawa M, Miyazono K, Aburatani H, Ishikawa S, Fukayama M.
  • Journal Title: Oncogene Volume: 33(19) Issue: 19 Pages: 2454-63
  • DOI: 10.1038/onc.2013.204
  • Peer Reviewed
• [Journal Article] The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway. (2014)
  • Author(s): Ui T, Morishima K, Saito S, Sakuma Y, Fujii H, Hosoya Y, Ishikawa S, Aburatani H, Fukayama M, Niki T, Yasuda Y.
  • Journal Title: Oncol Rep. Volume: 31(2) Issue: 2 Pages: 619-24
  • DOI: 10.3892/or.2013.2899
  • Peer Reviewed / Open Access
• [Journal Article] Fukayama M.Enrichment of stem-like cell population comprises transformation ability of Epstein-Barr virus latent membraneprotein 2A for non-transformed cells (2013)
  • Author(s): Nakaya T, Kikuchi Y, Kunita A, Ishikawa S, Matsusaka K, Hino R,Aburatani H
  • Journal Title: Virus Research Volume: Vol.174 Issue: 1-2 Pages: 108-115
  • DOI: 10.1016/j.virusres.2013.03.009
  • Peer Reviewed
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. (2013)
  • Author(s): Kon A, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 10 Pages: 1232-1237
  • DOI: 10.1038/ng.2731
  • Peer Reviewed
• [Journal Article] Lung cancer with loss of BRG1?BRM,shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. (2013)
  • Author(s): Matsubara D, Murakami Y, Niki T et al.
  • Journal Title: Cancer Sci Volume: 104 Issue: 2 Pages: 266-273
  • DOI: 10.1111/cas.12065
  • Peer Reviewed
• [Journal Article] Genome-wide single nucleotide polymorphism arrays as a diagnostic tool in patients with synchronous endometrial and ovarian cancer. (2012)
  • Author(s): Ikeda Y, Oda K, Nakagawa S
  • Journal Title: Int J Gynecol Cancer Volume: 22(5） Issue: 5 Pages: 725-31
  • DOI: 10.1097/igc.0b013e31824c6ea6
  • Peer Reviewed
• [Journal Article] Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. (2012)
  • Author(s): Matsubara D, Murakami Y, Niki T et al.
  • Journal Title: J Thorac Oncol Volume: 7 Issue: 12 Pages: 1872-1876
  • DOI: 10.1097/jto.0b013e3182721ed1
  • Peer Reviewed
• [Journal Article] ARID1Aexpression loss in gastric cancer: pathway-dependent roles with and without Epstein-Barr virus infection and microsatellite instability (2012)
  • Author(s): Abe H, Maeda D, Hino R, Otake Y, Isogai M, Ushiku AS, Matsusaka K,Kunita A, Ushiku T, Uozaki H,Tateishi Y, Hishima T, Iwasaki Y, Ishikawa S, Fukayama M
  • Journal Title: Virchows Archiv Volume: Vol.461 Issue: 4 Pages: 367-77
  • DOI: 10.1007/s00428-012-1303-2
  • Peer Reviewed
• [Journal Article] 臨床病理検査におけるゲノミクス (2011)
  • Author(s): 石川俊平、吉本倫子、馬場洋介
  • Journal Title: 病理と臨床増刊病理診断に役立つ分子生物学 Volume: 29 Pages: 492-507
• [Journal Article] 癌のデジタルトランスクリプトーム解析 (2011)
  • Author(s): 石川俊平
  • Journal Title: 医学のあゆみ特集 Volume: 36 Pages: 593-598
• [Journal Article] ASCL1-coexpression profiling but not single gene expression profiling defines lung adenocarcinomas of neuroendocrine nature with poor prognosis (2011)
  • Author(s): Fujiwara T, Aburatani H, et al.
  • Journal Title: Lung Cancer Volume: 75 Issue: 1 Pages: 119-25
  • DOI: 10.1016/j.lungcan.2011.05.028
  • Peer Reviewed
• [Journal Article] Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells (2011)
  • Author(s): Watanabe, A., et al
  • Journal Title: Proceedings of National Academy of Science U.S.A. Volume: 108 Issue: 30 Pages: 12384-12389
  • DOI: 10.1073/pnas.0906930108
  • Peer Reviewed
• [Journal Article] DNA Methylation Profiling of Embryonic Stem Cell Differentiation into the Three Germ Layers (2011)
  • Author(s): Isagawa T, Nagae G, Shiraki N, Fujita T, Sato N, Ishikawa S, Kume S, Aburatani H
  • Journal Title: PLoS ONE Volume: 6(10) Issue: 10 Pages: e26052-e26052
  • DOI: 10.1371/journal.pone.0026052
  • Peer Reviewed
• [Journal Article] B-catenin (CTNNB1) S33C mutation in ovarian microcystic stromal tumors (2011)
  • Author(s): Maeda D, Shibahara J, Sakuma T, Isobe M, Teshima S, Mori M, Oda K, Nakagawa S, Taketani Y, Ishikawa S, Fukayama M
  • Journal Title: Am J Surg Pathol Volume: 35 Issue: 10 Pages: 1429-1440
  • DOI: 10.1097/pas.0b013e31822d6c71
  • Peer Reviewed
• [Journal Article] Claudin-18 is an early-stage marker of pancreatic carcinogenesis (2011)
  • Author(s): Tanaka M, Shibahara J, Fukushima N, Shinozaki A, Umeda M, Ishikawa S, Kokudo N, Fukayama M
  • Journal Title: J Histochem Cytochem Volume: 59 Issue: 10 Pages: 942-952
  • DOI: 10.1369/0022155411420569
  • Peer Reviewed
• [Journal Article] Tissue-specific demethylation in CpG-poor promoters during cellular differentiation (2011)
  • Author(s): Nagae G, Isagawa T, Shiraki N, Fujita T, Yamamoto S, Tsutsumi S, Nonaka A,Yoshiba S, Matsusaka K, Midorikawa Y,Ishikawa S, Soejima H, Fukayama M,Suemori H, Nakatsuji N, Kume S,Aburatani H
  • Journal Title: Hum Mol Genetics Volume: 20(14) Issue: 14 Pages: 2710-21
  • DOI: 10.1093/hmg/ddr170
  • Peer Reviewed
• [Journal Article] 癌のデジタルトランスクリプトーム解析 (2011)
  • Author(s): 石川俊平
  • Journal Title: 医学のあゆみ Volume: 236 Pages: 593-598
• [Journal Article] Co-activation of epidermal growth factor receptor and c-MET defines a distinct subset of lung adenocarcinomas. (2010)
  • Author(s): Matsubara D, Ishikawa S, Sachiko O, Aburatani H, Fukayama M, Niki T.
  • Journal Title: Am J Pathol. Volume: 177 Pages: 2191-2204
  • Peer Reviewed
• [Presentation] Discovery of recurrent gain-of-function mutations of RHOA in diffuse-type gastric cancer (2014)
  • Author(s): Shumpei Ishikawa, Miwako Kakiuchi, Hiroki Ueda, Hiroto Katou, Masashi Fukayama, Hiroyuki Aburatani
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜、日本
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Discovery of Frequent Gain-offunction Mutation in Diffuse-type Gastric Carcinoma (2014)
  • Author(s): Shumpei Ishikawa
  • Organizer: 2014 SNUCRI Cancer Symposium
  • Place of Presentation: Mokpo, Korea
  • Year and Date: 2014-04-16 – 2014-04-19
  • Invited
• [Presentation] Transcriptome across Diverse Biological Species in Human Gastric Environment (2014)
  • Author(s): Hiroto Katoh, Daisuke Komura and Shumpei Ishikawa
  • Organizer: 平成25年度「がん支援」公開シンポジウム
  • Place of Presentation: 東京（一橋講堂）
• [Presentation] 胃癌組織や胃粘膜組織におけるメタトランスクリプトーム解析 (2013)
  • Author(s): 石川俊平
  • Organizer: 第61回(社)日本病理学会関東支部学術集会
  • Place of Presentation: 東京（東京大学鉄門講堂）
  • Invited
• [Presentation] 細胞間相互作用のシーケンシング (2012)
  • Author(s): 石川俊平
  • Organizer: 日本分子生物学会 第12回 春季シンポジウム
  • Place of Presentation: 山梨県笛吹市
  • Year and Date: 2012-04-25
  • Invited
• [Presentation] Histone deacetylases as promising drug targets for treatment of esophageal squamous cell carcinoma. (2012)
  • Author(s): Morishima K, Saito S, Matsubara D, Hosoya Y, Sata N, Yasuda Y, Ishikawa S, Niki T.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Chicago
  • Year and Date: 2012-04-01
• [Presentation] Histopathologic and genetic features of lung adenocarcinomas with loss of chromatin remodeling factors, BRG-1 and BRM. (2012)
  • Author(s): Matsubara D, Kishaba Y, Ishikawa S, Fukayama M, Niki T.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Chicago
  • Year and Date: 2012-04-01
• [Presentation] Systematic profiling of druggable cancer interactome (2011)
  • Author(s): Shumpei Ishikawa
  • Organizer: JCA-AACR Joint Symposium 2011
  • Place of Presentation: Nagoya, Japan(愛知県)(招待講演)
  • Year and Date: 2011-10-03
• [Presentation] Comprehensive analysis of paired cancer-normal tissue from digital transcriptome data. (2011)
  • Author(s): 石川俊平
  • Organizer: Human Genome Meeting, 2010
  • Place of Presentation: International Convention Center, Dubai, UAE
  • Year and Date: 2011-03-16
• [Presentation] トランスクリプトームシーケンシングによる癌の新規メカニズムの解析 (2011)
  • Author(s): 石川俊平
  • Organizer: がん研究分野の特性等を踏まえた支援活動公開シンポジウム
  • Place of Presentation: 一橋学術総合センター(東京都)
  • Year and Date: 2011-02-09
• [Remarks] 研究室ホームページ
  • URL: http://www.tmd.ac.jp/gpat/