An integrated genomic analysis on evolution of cancer cell population

2016 Fiscal Year Annual Research Report

• Project/Area Number: 24221011
• Research Institution: The University of Tokyo
• Principal Investigator: 油谷 浩幸 東京大学, 先端科学技術研究センター, 教授 (10202657)
• Project Period (FY): 2012-05-31 – 2017-03-31
• Keywords: ゲノム / エピゲノム / ドライバー変異 / 微小環境 / ノンコーディングRNA / 腫瘍内多様性

Outline of Annual Research Achievements

1．肝細胞がんについて早期肝がんと進行がんの統合ゲノム解析を行い、活性化ドライバー変異の標的遺伝子の活性化と当該遺伝子のDNA脱メチル化が相関することが見出された。一方、DNAメチル化プロファイルに基づく症例層別化を試みたところ、エピジェノタイプによるサブ集団は早期肝がんの段階で既に形成されており、肝炎ウイルスタイプや変異ドライバー遺伝子とも関連する傾向が認められ、ゲノム及びエピゲノム変異の組み合わせが腫瘍の発生・進展において重要であると考えられた。
2．オリゴデンドログリオーマの複数部位および再発腫瘍の解析から、初発時から再発時それぞれに固有の遺伝子変異が認められ、神経膠腫のゲノム多様性を示すものの、悪性化を強力に促すドライバー変異の獲得はみられず、DNAメチル化プロファイルも安定していることが認められた。
3．腫瘍増殖に関わる長鎖ノンコーディングRNA（ncRNA）の同定を進めた。β-catenin のChIP-seqおよびRNA-seq解析より、β-cateninにより直接転写誘導され、肝細胞がんや大腸がんでそれぞれCTNNB1あるいはAPC変異を有する症例において高発現を示すncRNAを同定した。β-カテニン標的遺伝子の転写調節に関与する可能性が高く、PRC2と相互作用することでクロマチン状態を制御すると考えられた。一方、β-カテニンおよび低栄養下で誘導されるncRNAも同定され、腫瘍悪性化に関わると考えられた。
4．腫瘍内微小環境においては低pH状態が形成されるが、酸性環境下（pH6.8）においてSREBP2が活性化され、酢酸代謝に関わるACSS2などの遺伝子群を誘導し、腫瘍細胞増殖をもたらすことを明らかにした。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Differences in genetic and epigenetic alterations between von Hippel-Lindau disease-related and sporadic hemangioblastomas of the central nervous system. (2017)
  • Author(s): Takayanagi S, Mukasa A, Tanaka S, Nomura M, Omata M, Yanagisawa S, Yamamoto S, Ichimura K, Nakatomi H, Ueki K, Aburatani H, Saito N
  • Journal Title: Neuro Oncol. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1093/neuonc/nox034
  • Peer Reviewed
• [Journal Article] Genetic and epigenetic stability of oligodendrogliomas at recurrence. (2017)
  • Author(s): Aihara K, Mukasa A, Nagae G, Nomura M, Yamamoto S, Ueda H, Tatsuno K, Shibahara J, Takahashi M, Momose T, Tanaka S, Takayanagi S, Yanagisawa S, Nejo T, Takahashi S, Omata M, Otani R, Saito K, Narita Y, Nagane M, Nishikawa R, Ueki K, Aburatani H, Saito N
  • Journal Title: Acta Neuropathol Commun. Volume: 5 Pages: 18
  • DOI: 10.1186/s40478-017-0422-z
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression. (2017)
  • Author(s): Kondo A, Yamamoto S, Nakaki R, Shimamura T, Hamakubo T, Sakai J, Kodama T, Yoshida T, Aburatani H, Osawa T.
  • Journal Title: Cell Rep. Volume: 18 Pages: 2228-2242
  • DOI: 10.1016/j.celrep.2017.02.006
  • Peer Reviewed / Open Access
• [Journal Article] CellTree: an R/bioconductor package to infer the hierarchical structure of cell populations from single-cell RNA-seq data (2017)
  • Author(s): duVerle DA, Yotsukura S, Nomura S, Aburatani H, Tsuda K
  • Journal Title: BMC Bioinformatics Volume: 17 Pages: 363
  • DOI: 10.1186/s12859-016-1175-6
  • Peer Reviewed / Open Access
• [Journal Article] CASTIN: a system for comprehensive analysis of cancer-stromal interactome. (2016)
  • Author(s): Komura D, Isagawa T, Kishi K, Suzuki R, Sato R, Tanaka M, Katoh H, Yamamoto S, Tatsuno K, Fukayama M, Aburatani H, Ishikawa S
  • Journal Title: BMC Genomics Volume: 17 Pages: 899
  • DOI: 10.1186/s12864-016-3207-z
  • Peer Reviewed / Open Access
• [Journal Article] TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection. (2016)
  • Author(s): Namba-Fukuyo H, Funata S, Matsusaka K, Fukuyo M, Rahmutulla B, Mano Y, Fukayama M, Aburatani H, Kaneda A
  • Journal Title: Oncotarget Volume: 7 Pages: 81512-81526
  • DOI: 10.18632/oncotarget.13130
  • Peer Reviewed / Open Access
• [Journal Article] Base-Resolution Analysis of 5-Hydroxymethylcytosine by One-Pot Bisulfite-Free Chemical Conversion with Peroxotungstate. (2016)
  • Author(s): Hayashi G, Koyama K, Shiota H, Kamio A, Umeda T, Nagae G, Aburatani H, Okamoto A.
  • Journal Title: J Am Chem Soc. Volume: 138 Pages: 14178-14181
  • DOI: 10.1021/jacs.6b06428
  • Peer Reviewed
• [Journal Article] MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53. (2016)
  • Author(s): Makii C, Oda K, Ikeda Y, Sone K, Hasegawa K, Uehara Y, Nishijima A, Asada K, Koso T, Fukuda T, Inaba K, Oki S, Machino H, Kojima M, Kashiyama T, Mori-Uchino M, Arimoto T, Wada-Hiraike O, Yano KK, Fujiwara K, Aburatani H, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: 7 Pages: 75328-75338
  • DOI: 10.18632/oncotarget.12175.
  • Peer Reviewed / Open Access
• [Journal Article] Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer. (2016)
  • Author(s): Matsusaka K, Ushiku T, Urabe M, Fukuyo M, Abe H, Ishikawa S, Seto Y, Aburatani H, Hamakubo T, Kaneda A, Fukayama M.
  • Journal Title: Oncotarget Volume: 7 Pages: 64168-64181
  • DOI: 10.18632/oncotarget.11510
  • Peer Reviewed / Open Access
• [Journal Article] Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program. (2016)
  • Author(s): Vasilaki E, Morikawa M, Koinuma D, Mizutani A, Hirano Y, Ehata S, Sundqvist A, Kawasaki N, Cedervall J, Olsson AK, Aburatani H, Moustakas A, Miyazono K, Heldin CH
  • Journal Title: Sci Signal. Volume: 9 Pages: 84a
  • DOI: 10.1126/scisignal.aag3232
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth. (2016)
  • Author(s): Obinata D, Takayama K, Fujiwara K, Suzuki T, Tsutsumi S, Fukuda N, Nagase H, Fujimura T, Urano T, Homma Y, Aburatani H, Takahashi S, Inoue S
  • Journal Title: Oncogene Volume: 35 Pages: 6350-6358
  • DOI: 10.1038/onc.2016.171
  • Peer Reviewed
• [Journal Article] Network-based analysis for identification of candidate genes for colorectal cancer progression. (2016)
  • Author(s): Tsuji S, Midorikawa Y, Seki M, Takayama T, Sugiyama Y, Aburatani H
  • Journal Title: Biochem Biophys Res Commun. Volume: 476 Pages: 534-40
  • DOI: 10.1016/j.bbrc.2016.05.158
  • Peer Reviewed
• [Journal Article] Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens. (2016)
  • Author(s): Matsusaka K, Ishikawa S, Nakayama A, Ushiku T, Nishimoto A, Urabe M, Kaneko N, Kunita A, Kaneda A, Aburatani H, Fujishiro M, Seto Y, Fukayama M.
  • Journal Title: PLoS One Volume: 11 Pages: e0154430
  • DOI: 10.1371/journal.pone.0154430
  • Peer Reviewed / Open Access
• [Journal Article] Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. (2016)
  • Author(s): Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y, Tanaka H, Taniguchi H, Kawakami Y, Ueno M, Gotoh K, Ariizumi SI, Wardell CP, Hayami S, Nakamura T, Aikata H, Arihiro K, Boroevich KA, Abe T, Nakano K, Maejima K, Sasaki-Oku A, Ohsawa A, Shibuya T, Nakamura H, Hama N, …, Aburatani H, Shibata T, Nakagawa H.
  • Journal Title: Nat Genet. Volume: 48 Pages: 500-9
  • DOI: 10.1038/ng.3547
  • Peer Reviewed
• [Journal Article] Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis. (2016)
  • Author(s): 10)Takane K, Matsusaka K, Ota S, Fukuyo M, Yue Y, Nishimura M, Sakai E, Matsushita K, Miyauchi H, Aburatani H, Nakatani Y, Takayama T, Matsubara H, Akagi K, Kaneda A.
  • Journal Title: Oncotarget. Volume: 7 Pages: 84003-84016
  • DOI: 10.18632/oncotarget.11510
  • Peer Reviewed / Open Access
• [Presentation] Nucleome analysis: transcriptional regulation by chromatin interaction (2016)
  • Author(s): 油谷浩幸
  • Organizer: 39th Annual Meeting of Molecular Biology Society Japan
  • Place of Presentation: 横浜
  • Year and Date: 2016-12-01
  • Invited
• [Presentation] ゲノム研究と医療の融合 (2016)
  • Author(s): 油谷浩幸
  • Organizer: 日本オミックス医療学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-18
  • Invited
• [Presentation] Progression of hepatocellular carcinoma: Interplay of genome and epigenome (2016)
  • Author(s): 油谷浩幸
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] Interplay of genome and epigenome in progression of hepatocellular carcinoma (2016)
  • Author(s): 油谷浩幸
  • Organizer: 12th Scientific Workshop, International Cancer Genome Consortium
  • Place of Presentation: ボストン、アメリカ
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Progression of hepatocellular carcinoma: interplay of genome and epigenome (2016)
  • Author(s): 油谷浩幸
  • Organizer: The 41st Naito Conference on Tumor Heterogeneity and Plasticity
  • Place of Presentation: 札幌
  • Year and Date: 2016-07-06
  • Int'l Joint Research / Invited
• [Presentation] Methylation profiling of hepatocellular carcinoma (2016)
  • Author(s): 油谷浩幸
  • Organizer: The 35th Sapporo International Cancer Symposium 2016
  • Place of Presentation: 札幌
  • Year and Date: 2016-06-24
  • Int'l Joint Research / Invited
• [Presentation] 高悪性度漿液性卵巣がんのゲノム変異と化学療法感受性 (2016)
  • Author(s): 油谷浩幸
  • Organizer: 第20回日本がん分子標的治療学会
  • Place of Presentation: 別府
  • Year and Date: 2016-05-31
  • Invited
• [Presentation] Early hepatocellular carcinoma (2016)
  • Author(s): 油谷浩幸
  • Organizer: The 102nd General Meeting of the Japanese Society of Gastroenterology The 5th International Forum
  • Place of Presentation: 東京
  • Year and Date: 2016-04-22
  • Invited
• [Presentation] Integrated genomic analysis of liver cancer progression (2016)
  • Author(s): 油谷浩幸
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都
  • Year and Date: 2016-04-04
  • Int'l Joint Research / Invited
• [Remarks] 東京大学先端科学技術研究センター ゲノムサイエンス分野
  • URL: http://www.genome.rcast.u-tokyo.ac.jp/