Integrated analysis of genetic and epigenetic alterations in hepatocellular carcinoma.

• Project/Area Number: 26293172
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Marusawa Hiroyuki 京都大学, 医学(系)研究科(研究院), 准教授 (80324630)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 肝癌 / 遺伝子変異 / AID

Outline of Final Research Achievements

Liver cancers, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, generally arise in liver chronically inflamed due to various diseases such as hepatitis virus infection and steatohepatitis. Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. We found that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues.

Research Products

• [Journal Article] MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development. (2016)
  • Author(s): Eso Y, Takai A, Matsumoto T, Inuzuka T, Horie T, Ono K, Uemoto S, Lee K, Edelmann W, Chiba T, Marusawa H
  • Journal Title: Cancer Research Volume: 76 Pages: 4383-4393
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma. (2016)
  • Author(s): Ki Kim S, Ueda Y, Hatano E, Kakiuchi N, Takeda H, Goto T, Shimizu T, Yoshida K, Ikura Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Uemoto S, Chiba T, Ogawa S, Marusawa H.
  • Journal Title: Int J Cancer. Volume: 139 Issue: 11 Pages: 2512-2518
  • DOI: 10.1002/ijc.30379
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis (2015)
  • Author(s): Matsumoto T, Shimizu T, Nishijima N, Ikeda A, Eso Y, Matsumoto Y, Chiba T, Marusawa H
  • Journal Title: Carcinogenesis Volume: 36 Issue: 8 Pages: 904-913
  • DOI: 10.1093/carcin/bgv065
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations. (2015)
  • Author(s): Sawai Y, Kodama Y, Shimizu T, Ota Y, Maruno T, Eso Y, Kurita A, Shiokawa M, Tsuji Y, Uza N, Matsumoto Y, Masui T, Uemoto S, Marusawa H, Chiba T.
  • Journal Title: Cancer Res. Volume: 15 Issue: 16 Pages: 32923301-32923301
  • DOI: 10.1158/0008-5472.can-14-3028
  • Peer Reviewed
• [Journal Article] Exploring the Mechanisms of Gastrointestinal Cancer Development Using Deep Sequencing Analysis (2015)
  • Author(s): Matsumoto T, Shimizu T, Takai A, Marusawa H
  • Journal Title: Cancers (Basel) Volume: 7 Issue: 2 Pages: 1037-1051
  • DOI: 10.3390/cancers7020823
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. (2014)
  • Author(s): Shimizu T, Marusawa H, Matsumoto Y, Inuzuka T, Ikeda A, Fujii Y, Minamiguchi S, Miyamoto S, Kou T, Sakai Y, Crabtree JE, Chiba T.
  • Journal Title: Gastroenterology Volume: 147 Issue: 2 Pages: 407-417
  • DOI: 10.1053/j.gastro.2014.04.036
  • NAID: 120005466713
  • Peer Reviewed / Open Access
• [Journal Article] Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma. (2014)
  • Author(s): Ikeda A, Shimizu T, Matsumoto Y, Fujii Y, Eso Y, Inuzuka T, Mizuguchi A, Shimizu K, Hatano E, Uemoto S, Chiba T, Marusawa H
  • Journal Title: Gastroenterology Volume: 146 Issue: 1 Pages: 222-232
  • DOI: 10.1053/j.gastro.2013.09.025
  • NAID: 120005372982
  • Peer Reviewed / Open Access
• [Journal Article] A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations. (2014)
  • Author(s): Soo Ki Kim, Akihiro Nasu, Junji Komori, Takahiro Shimizu, Yuko Matsumoto, Yasuko Minaki, Kenji Kohno, Kazuharu Shimizu, Shinji Uemoto, Tsutomu Chiba, Hiroyuki Marusawa.
  • Journal Title: International Journal of Cancer Volume: 134 Issue: 5 Pages: 1067-76
  • DOI: 10.1002/ijc.28445
  • Peer Reviewed / Open Access
• [Presentation] Genomic approaches to uncover clonal structure and oncogenic potential of liver cirrhosis (2016)
  • Author(s): Kim SK, Ogawa S, Marusawa H
  • Organizer: 第58回日本消化器病学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-11-03
• [Presentation] 肝炎症発癌におけるDNAミスマッチ修復遺伝子MSH2の発現低下と変異パターンの関連性 (2016)
  • Author(s): 恵荘裕嗣、高井淳、千葉勉、妹尾浩、丸澤宏之
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] EpCAM陽性肝幹/前駆細胞は肝細胞癌の起源となる (2016)
  • Author(s): 松本知訓、高井淳、恵荘裕嗣、千葉勉、妹尾浩、丸澤宏之
  • Organizer: 第75回日本癌学会学術総
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] 肝癌の発生母地としての肝硬変組織に潜在するゲノム異常 (2016)
  • Author(s): 金秀基、吉田健一、垣内伸之、上田佳秀、南口早智子、海道利実、白石友一、宮野悟、羽賀博典、上本伸二、妹尾浩、小川誠司、丸澤宏之
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] 消化器癌のゲノムワイドなコピー数異常と全ゲノムコピー数解析の実際 (2015)
  • Author(s): 丸澤宏之
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県 名古屋国際会議場
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] 脂肪肝疾患に由来するヒト肝がんのゲノム異常の特性 (2015)
  • Author(s): 金秀基、後藤知之、千葉勉、丸澤宏之
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] 膵癌進展におけるactivation-induced cytidine deaminase(AID)の役割 (2015)
  • Author(s): 大田悠司、澤井勇吾、児玉裕三、丸澤宏之、千葉勉
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] 食道扁平上皮癌の染色体コピー数異常における予後関連因子の検討 (2015)
  • Author(s): 後藤知之、島田裕、金秀基、清水孝洋、髙井淳、千葉勉、丸澤宏之
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] NBNC肝癌におけるNASH肝癌の位置づけとゲノム異常の網羅的解析 (2014)
  • Author(s): 金秀基、波多野悦朗、丸澤宏之
  • Organizer: 第56回日本消化器病学会大会
  • Place of Presentation: ポートピアホテル本館 兵庫県 神戸市
  • Year and Date: 2014-10-25
• [Presentation] 慢性炎症は転写上昇を介してゲノム変異導入を亢進し肝発癌を促進する (2014)
  • Author(s): 松本知訓、西島規浩、千葉勉、丸澤宏之
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜市 神奈川県
  • Year and Date: 2014-09-25
• [Presentation] Mutation profiles of hepatocellular carcinoma developed in nonalcoholic fatty liver disease. 脂肪性肝疾患に発生する肝癌のゲノム異常解析 (2014)
  • Author(s): 金秀基、千葉勉、丸澤宏之
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜市 神奈川県
  • Year and Date: 2014-09-25