Clarification of genome/epigenome interaction in microsatellite instable gastric cancer

• Project/Area Number: 19K07457
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Chiba University
• Principal Investigator: Matsusaka Keisuke 千葉大学, 医学部附属病院, 准教授 (40610150)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: エピジェネティクス / 胃癌 / 遺伝子変異 / 早期細胞老化 / TP53 / マイクロサテライト不安定性 / 胃癌の分子基盤 / ゲノム異常 / エピゲノム異常

Outline of Research at the Start

DNAメチル化と遺伝子変異が高度に蓄積したマイクロサテライト不安定性(MSI)胃癌に着目したところ、共通したゲノム異常、MLH1の発現消失、エピゲノム修飾因子の不活化を見出した。そこで、本研究では以下の課題について取り組み、MSI胃癌の本態解明を目指す。(1)shRNAライブラリーと化合物を用いたTP53非依存的な早期細胞老化経路の解明
(2)クロマチン立体構造解析によるMLH1のエンハンサー領域の同定とMLH1不活化機構の本態解明
(3)エピゲノム修飾因子の不活化がエピゲノム変化に及ぼす影響の検討

Outline of Final Research Achievements

Microsatellite instability (MSI)-positive gastric cancer (GC) showed high DNA methylation epigenotype and highly mutated phenotype via the comprehensive DNA methylation analysis and target-exome sequencing analysis. The gene mutation in MSI-positive GC was found in RAS-related genes and TGFβ signaling pathway-related genes, whereas TP53 had no mutation. The genes contributing to premature senescence in a TP53-independent manner were successfully extracted by genome-wide screening using the shRNA library. We identified chemical compounds to exert antitumor effects in TP53 wild-type cancer cells. This result suggested the possibility of novel therapeutic strategies using wild-type TP53.

Academic Significance and Societal Importance of the Research Achievements

MSI陽性胃癌は多くの遺伝子にDNAメチル化と変異を伴っていることから、これまで機能的な意義づけが十分になされていなかった。本解析によりDNAメチル化と遺伝子変異による相乗効果が確認され、TP53変異とは独立した早期細胞老化に寄与する遺伝子の同定に成功した。また、野生型TP53を有する癌細胞の解析により、TP53下流の経路は保たれており、野生型TP53を利用した治療戦略が構築できる可能性が得られた。これは胃癌のみならず多種多様な腫瘍にも応用可能である潜在性を有しており、今後の展開が期待される。

Research Products

• [Journal Article] Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis (2021)
  • Author(s): Hata Atsushi、Nakajima Takahiro、Matsusaka Keisuke、Fukuyo Masaki、Nakayama Manabu、Morimoto Junichi、Ito Yuki、Yamamoto Takayoshi、Sakairi Yuichi、Rahmutulla Bahityar、Ota Satoshi、Wada Hironobu、Suzuki Hidemi、Iwata Takekazu、Matsubara Hisahiro、Ohara Osamu、Yoshino Ichiro、Kaneda Atsushi
  • Journal Title: International Journal of Cancer Volume: - Issue: 12 Pages: 3008-3018
  • DOI: 10.1002/ijc.33499
  • Peer Reviewed
• [Journal Article] Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein‐Barr virus‐positive gastric cancer (2021)
  • Author(s): Li Wenzhe、Okabe Atsushi、Usui Genki、Fukuyo Masaki、Matsusaka Keisuke、Rahmutulla Bahityar、Mano Yasunobu、Hoshii Takayuki、Funata Sayaka、Hiura Nobuhiro、Fukayama Masashi、Tan Patrick、Ushiku Tetsuo、Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 112 Issue: 8 Pages: 3349-3362
  • DOI: 10.1111/cas.14978
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Collision of Epstein?Barr virus-positive and -negative gastric cancer, diagnosed by molecular analysis: a case report (2021)
  • Author(s): Miyabe Ken、Saito Motonobu、Koyama Kei、Umakoshi Michinobu、Ito Yukinobu、Yoshida Makoto、Kudo-Asabe Yukitsugu、Saito Katsuharu、Nanjo Hiroshi、Maeda Daichi、Matsusaka Keisuke、Goto Akiteru、Kono Koji
  • Journal Title: BMC Gastroenterology Volume: 21 Issue: 1 Pages: 97-97
  • DOI: 10.1186/s12876-021-01683-y
  • Peer Reviewed / Open Access
• [Journal Article] The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2 (2021)
  • Author(s): Maimaiti Maihulan、Sakamoto Shinichi、Sugiura Masahiro、Kanesaka Manato、Fujimoto Ayumi、Matsusaka Keisuke、Xu Minhui、Ando Keisuke、Saito Shinpei、Wakai Ken、Imamura Yusuke、Nakayama Keiichi、Kanai Yoshikatsu、Kaneda Atsushi、Ikehara Yuzuru、Ikeda Jun-Ichiro、Anzai Naohiko、Ichikawa Tomohiko
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 11478-11478
  • DOI: 10.1038/s41598-021-90748-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of clonal immunoglobulin λ light-chain gene rearrangements in AL amyloidosis using next-generation sequencing (2021)
  • Author(s): Kimura K、Tsukamoto S、Miyazaki K、Kawajiri-Manako C、Ishii A、Rahmutulla B、Fukuyo M、Oshima-Hasegawa N、Mitsukawa S、Takeda Y、Mimura N、Takeuchi M、Ohwada C、Iseki T、Matsusaka K、Sanada M、Yokote K、Kaneda A、Ishida T、Suzuki K、Nakaseko C、Sakaida E
  • Journal Title: Experimental Hematology Volume: 101-102 Pages: 34-41
  • DOI: 10.1016/j.exphem.2021.08.001
  • Peer Reviewed / Open Access
• [Journal Article] Solid serous neoplasm of the pancreas with locally aggressive behaviors (2021)
  • Author(s): Kouchi Yusuke、Yamashita Kazushi、Harada Sakurako、Shinomiya Yoshiki、Mishima Takashi、Takano Shigetsugu、Matsusaka Keisuke、Nasu Katsuhiro、Ikeda Jun‐ichiro、Ohtsuka Masayuki、Kishimoto Takashi
  • Journal Title: Pathology International Volume: 71 Issue: 11 Pages: 795-797
  • DOI: 10.1111/pin.13163
  • Peer Reviewed
• [Journal Article] Genetic profiles of Barrett’s esophagus and esophageal adenocarcinoma in Japanese patients (2021)
  • Author(s): Tokunaga Mamoru、Okimoto Kenichiro、Akizue Naoki、Ishikawa Kentaro、Hirotsu Yosuke、Amemiya Kenji、Ota Masayuki、Matsusaka Keisuke、et al.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 17671-17671
  • DOI: 10.1038/s41598-021-97249-9
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer. (2020)
  • Author(s): Kurokawa T, Nakagawa T, Matsusaka K, Fukuyo M, Mima M, Misawa K, Rahmutulla B, Ikeda JI, Hanazawa T, Okamoto Y, Kaneda A
  • Journal Title: Cancer Sci. Volume: 111 Issue: 4 Pages: 1407-1416
  • DOI: 10.1111/cas.14338
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stratification of HPV-associated and HPV-negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes. (2020)
  • Author(s): Nakagawa T, Matsusaka K, Misawa K, Ota S, Fukuyo M, Rahmutulla B, Kunii N, Sakurai D, Hanazawa T, Matsubara H, Okamoto Y, Kaneda A
  • Journal Title: Int J Cancer. Volume: 146 Issue: 9 Pages: 2460-2474
  • DOI: 10.1002/ijc.32890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epstein‐Barr virus positive gastric cancer involves enhancer activation through ATF3 (2020)
  • Author(s): Asakawa Yuta、Okabe Atsushi、Fukuyo Masaki、Li Wenzhe、Ikeda Eriko、Mano Yasunobu、Funata Sayaka、Namba Hiroe、Fujii Takahiro、Kita Kazuko、Matsusaka Keisuke、Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 00 Issue: 5 Pages: 1-11
  • DOI: 10.1111/cas.14370
  • Peer Reviewed / Open Access
• [Journal Article] High expression of CXCL14 is a biomarker of lung adenocarcinoma with micropapillary pattern (2020)
  • Author(s): Sata Yuki, Nakajima Takahiro, Fukuyo Masaki, Matsusaka Keisuke, Hata Atsushi, Morimoto Junichi, Rahmutulla Bahityar, Ito Yuki, Suzuki Hidemi, Yoshino Ichiro, Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 111 Issue: 7 Pages: 2588-2597
  • DOI: 10.1111/cas.14456
  • Peer Reviewed / Open Access
• [Journal Article] Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma (2020)
  • Author(s): Okabe Atsushi, Huang Kie Kyon, Matsusaka Keisuke, Fukuyo Masaki, Xing Manjie, Ong Xuewen, Hoshii Takayuki, Usui Genki, Seki Motoaki, Mano Yasunobu, Rahmutulla Bahityar, Kanda Teru, Suzuki Takayoshi, Rha Sun Young, Ushiku Tetsuo, Fukayama Masashi, Tan Patrick, Kaneda Atsushi
  • Journal Title: Nature Genetics Volume: 52 Issue: 9 Pages: 919-930
  • DOI: 10.1038/s41588-020-0665-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Thirty years of Epstein-Barr virus-associated gastric carcinoma. (2020)
  • Author(s): Fukayama M, Abe H, Kunita A, Shinozaki-Ushiku A, Matsusaka K, Ushiku T, Kaneda A.
  • Journal Title: Virchows Arch Volume: 476 Issue: 3 Pages: 353-365
  • DOI: 10.1007/s00428-019-02724-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis. (2020)
  • Author(s): Hata A, Nakajima T, Matsusaka K, Fukuyo M, Morimoto J, Yamamoto T, Sakairi Y, Rahmutulla B, Ota S, Wada H, Suzuki H, Matsubara H, Yoshino I, Kaneda A.
  • Journal Title: Int J Cancer Volume: 146 Issue: 2 Pages: 388-399
  • DOI: 10.1002/ijc.32532
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epstein-Barr virus-positive gastric cancer involves enhancer activation through activating transcription factor 3. (2020)
  • Author(s): Asakawa Y, Okabe A, Fukuyo M, Li W, Ikeda E, Mano Y, Funata S, Namba H, Fujii T, Kita K, Matsusaka K, Kaneda A.
  • Journal Title: Cancer Sci. Volume: －
  • Peer Reviewed / Open Access / Int'l Joint Research