Elucidation of therapeutic response mechanisms in liver cancer by integrated genomic analysis using nucleic acids in peripheral blood

• Project/Area Number: 19K17392
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Murakawa Miyako 東京医科歯科大学, 医学部附属病院, 助教 (20733851)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝細胞癌 / 遺伝子変異 / 肝炎ウイルス / cell free DNA / 肝癌 / ゲノム / 肝線維化 / iPS細胞

Outline of Research at the Start

近年、脂肪肝など非ウイルス性の背景を持つ肝癌が急増しているがそれらの病態に関わる癌ゲノム要因の詳細は不明であり、また全身化学療法の選択肢が多様化する中で治療反応性の規定因子の解明が求められている。本研究では、特殊な病態の肝癌や分子標的治療効果に関与するゲノム要因を解明するために、①血漿中の微量核酸を用いた癌関連遺伝子変異の探索、その結果と臨床情報の対比に基づき②肝癌の病態および③全身化学療法の治療反応性を規定するゲノム要因を同定する。さらに、見出したゲノム異常の機能解明のため④ヒトiPS細胞由来肝細胞を用いて機能解析を行い、精密医療に向けた知的基盤形成を目指す。

Outline of Final Research Achievements

We investigated the patterns of genetic changes characteristic of the cancer using surgical and blood specimens obtained from the patients treated for hepatocellular carcinoma. In particular, we analyzed the characteristics of hepatocellular carcinoma, which occurs despite viral control, and found that it has genomic mutations that are different from those under viral control and that carcinogenesis is also affected by liver fibrosis and inflammation, alcohol consumption, and diabetes. In addition, we confirmed that it is possible to evaluate the genomic characteristics of hepatocellular carcinoma, including TERT mutation, by analyzing DNA present in very small amounts in blood, and established a basis for analyzing genomic changes associated with the effects of anti-cancer agents on inoperable advanced cancer.

Academic Significance and Societal Importance of the Research Achievements

今回の研究では抗がん剤の治療効果に直結する肝癌遺伝子変化の同定には至らなかったが、Liquid biopsyにより肝癌の遺伝子解析が可能であることを示した点は、新規治療薬が承認され治療選択肢が広がっている現状において手術不能肝癌の最適な治療選択に向けた特徴の解明、新たな分類の可能性につながる。また、ウイルス制御下や非ウイルス性肝癌は手術不能な進行癌で発見される症例も多いが、臨床データベースを用いて肝癌の臨床的特徴とゲノム変化の関連を解析する中でFIB4-indexがウイルス制御下発癌の高リスク群の囲い込みに有用であることを見出したことは、効率的な癌サーベイランスに向けて社会的意義が大きい。

Research Products

• [Journal Article] Mac-2 binding protein glycosylation isomer as a novel predictive biomarker for patient survival after hepatitis C virus eradication by DAAs (2020)
  • Author(s): Nakagawa M, Nawa N, Takeichi E, Shimizu T, Tsuchiya J, Sato A, Miyoshi M, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Fujiwara T, Watanabe M, Tanaka Y, Asahina Y; Ochanomizu Liver Conference Study Group.
  • Journal Title: Journal of Gastroenterology Volume: 55 Issue: 10 Pages: 990-999
  • DOI: 10.1007/s00535-020-01715-6
  • Peer Reviewed / Open Access
• [Journal Article] Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts (2020)
  • Author(s): Sato A, Kakinuma S, Miyoshi M, Kamiya A, Tsunoda T, Kaneko S, Tsuchiya J, Shimizu T, Takeichi E, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Koshikawa N, Seiki S, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Hepatology Communications Volume: 4 Issue: 2 Pages: 235-254
  • DOI: 10.1002/hep4.1459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] .Association of serum IFN-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. (2019)
  • Author(s): Emi Inoue-Shinomiya, Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Sayuri Nitta, Fukiko Kawai-Kitahata, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Kazumoto Murata, Masashi Mizokami, Mamoru Watanabe.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 5 Pages: 500-511
  • DOI: 10.1111/hepr.13307
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Fibrocystin Promotes Interleukin-8-Dependent Proliferation and CTGF Production of Biliary Epithelium. (2019)
  • Author(s): Tsunoda T, Kakinuma S, Miyoshi M, Kamiya A, Kaneko S, Sato A, Tsuchiya J, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Sogo T, Komatsu H, Mukouchi R, Inui A, Fujisawa T, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Journal of Heptatology Volume: 印刷中 Issue: 1 Pages: 143-152
  • DOI: 10.1016/j.jhep.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients (2019)
  • Author(s): Nitta S, Asahina Y, Kato T, Tsuchiya J, Inoue-Shinomiya E, Sato A, Tsunoda T, Miyoshi M, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Hikita H, Takehara T, Watanabe M.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5722-5722
  • DOI: 10.1038/s41598-019-42114-z
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma‐like area and metachronous hepatocellular carcinoma (2019)
  • Author(s): Kawai-Kitahata F, Asahina Y, Kaneko S, Tsuchiya J, Sato A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Tanabe M, Sugawara E, Takemoto A, Ojima H, Sakamoto M, Muraoka M, Takano S, Maekawa S, Enomoto N and Watanabe M.
  • Journal Title: Hepatology Research Volume: 49 Issue: 12 Pages: 1466-1474
  • DOI: 10.1111/hepr.13403
  • Peer Reviewed / Open Access
• [Journal Article] Post SVRにおけるM2BPGiの意義 (2019)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Journal Title: 肝胆膵 特集/Post SVR時代のC型肝炎診療 Volume: 78-4 Pages: 607-614
• [Presentation] Poor improvement of on-treatment FIB-4 index after initiation of nucleos(t)ide analogs is associated with development of hepatocellular carcinoma in both cirrhotic and non-cirrhotic chronic hepatitis B patients. (2020)
  • Author(s): Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Taro Shimizu, Eiko Takeichi, Jun Tsuchiya, Ayako Sato, Masato Miyoshi, Fukiko Kawai-Kitahata, Sayuri Nitta, Yasuhiro Itsui, Sei Kakinuma, Seishin Azuma, Mamoru Watanabe.
  • Organizer: EASL The Digital International Liver Congress
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of cancer-related genes and aav/hepatitis b virus integration into genome on development of hepatocellular carcinoma in patients with prior hepatitis b virus infection. (2020)
  • Author(s): Fukiko Kawai-Kitahata, Yasuhiro Asahina , Sei Kakinuma, Miyako Murakawa, Sayuri Nitta, Masato Miyoshi, Ayako Sato, Jun Tsuchiya, Taro Shimizu, Eiko Takeichi, Mina Nakagawa, Yasuhiro Itsui, Seishin Azuma, Shinji Tanaka , Minoru Tanabe, Shinya Maekawa, Nobuyuki Enomoto and Mamoru Watanabe.
  • Organizer: EASL The Digital International Liver Congress
  • Int'l Joint Research
• [Presentation] 核酸アナログ治療下のB型慢性肝疾患における発癌予測因子の解析 (2020)
  • Author(s): 村川美也子、中川美奈、朝比奈靖浩
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] C型慢性肝疾患SVR後肝発癌予測因子の検討 (2020)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] SVR後の肝発癌、生存予測因子の解析 (2020)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] 核酸アナログによるB型肝炎ウイルス制御下の発癌に関連するon-treatment factorの探索 (2020)
  • Author(s): 村川美也子、中川美奈、朝比奈靖浩
  • Organizer: JDDW2020
• [Presentation] C型慢性肝疾患SVR後の肝発癌および予後の検討 (2020)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: JDDW2020
• [Presentation] 代償性・非代償性C型肝硬変の病態進展予測における肝硬度測定の有用性の検討 (2020)
  • Author(s): 村川美也子、朝比奈靖浩、青柳栄子、斉木有美、鈴木委久江、平地渉、宮崎健太郎、松本梨沙、市村直也、東田修二
  • Organizer: 第93回日本超音波医学会学術集会
• [Presentation] 核酸アナログによるHBV制御後の発癌予測因子の検討 (2020)
  • Author(s): 村川美也子、朝比奈靖浩、中川美奈、北畑富貴子、志水太郎、土屋淳、佐藤綾子、新田沙由梨、井津井康浩、東正新、柿沼晴
  • Organizer: 第56回日本肝癌研究会
• [Presentation] The association of serum IFN-λ3 levels with liver fibrosis and hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents (2019)
  • Author(s): Miyako Murakawa, Emi Inoue-Shinomiya, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Masato Miyoshi, Tomoyuki Tsunoda, Fukiko Kawai-Kitahata, Sayuri Nitta, Yasuhiro Itsui, Sei Kakinuma, Seishin Azuma, Mamoru Watanabe
  • Organizer: EASL The International Liver Congress 2019
  • Int'l Joint Research
• [Presentation] 核酸アナログ治療中および非治療のB型慢性肝疾患症例における発癌寄与因子の解析 (2019)
  • Author(s): 村川美也子、朝比奈靖浩、渡辺守
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] C型慢性肝疾患におけるSVR後発癌とIFN-λ3の関連 (2019)
  • Author(s): 村川美也子、四宮恵美、朝比奈靖浩、中川美奈、土屋淳、佐藤綾子、三好正人、角田正之、北畑富貴子、新田沙由梨、井津井康浩、東正新、柿沼晴、渡辺守
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] B型肝炎ウイルスキャリアにおけるHBs抗原陰性化および発がんに関わる臨床因子の検討 (2019)
  • Author(s): 村川美也子、中川美奈、土屋淳、佐藤綾子、三好正人、北畑富貴子、新田沙由梨、井津井康浩、東正新、柿沼晴、朝比奈靖浩
  • Organizer: JDDW2019 第23回日本肝臓学会大会
• [Presentation] 核酸アナログによるウイルス制御下のB型慢性肝疾患にお ける発癌寄与因子の検討 (2019)
  • Author(s): 村川美也子、朝比奈靖浩、渡辺守
  • Organizer: 第55回日本肝癌研究会
• [Presentation] Impact of HCV clearance on HCC development and patient survival: Propensity score-matched analysis of an ongoing database of 2173 CHC (2019)
  • Author(s): Mina Nakagawa, Yasuhiro Asahina, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Msato Miyosh, Emi Inoue, Fukiko Kawai-Kitahata, MIyako Murakawa, Sayuri Nitta, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Makoto Tomita, Mamoru Watanabe
  • Organizer: EASL The International Liver Congress 2019
  • Int'l Joint Research
• [Presentation] C型肝炎ウイルス排除後の肝発がんに関わるリスク因子と病態の解析 (2019)
  • Author(s): 朝比奈靖浩、村川美也子、中川美奈
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 背景肝の線維化からみた肝細胞癌における癌関連遺伝子変異とviral integrationの検討 (2019)
  • Author(s): 北畑富貴子、朝比奈靖浩、村川美也子、新田沙由梨、柿沼晴、角田知之 、三好正人、四宮恵美、佐藤綾子、土屋淳、井津井康浩、中川美奈、 東正新、田中真二、田邉稔、前川伸哉、榎本信幸、渡辺守
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] ウイルス制御下における肝発癌および長期予後―前向きコホートを用いたIFNベース治療とIFNフリー治療の比較検討― (2019)
  • Author(s): 中川美奈、朝比奈靖浩、村川美也子
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 細胆管細胞癌内の異なる表現型及び肝細胞癌における癌関連遺伝子の網羅的解析 (2019)
  • Author(s): 北畑富貴子、朝比奈靖浩、金子 俊、村川美也子、新田沙由梨、柿沼 晴、 三好正人、佐藤綾子、井津井康浩、中川美奈、東 正新、田邉 稔、菅原江美子、竹本 暁、坂元亨宇、尾島英知、村岡 優、前川伸哉 、榎本信幸 、渡辺 守
  • Organizer: 第55回日本肝癌研究会
• [Presentation] Comprehensive analysis of cancer gene mutations and viral integration in hepatocellular carcinoma arising from non-fibrotic liver (2019)
  • Author(s): Yasuhiro Asahina, Fukiko Kawai-Kitahata, Miyako Murakawa, Sayuri Nitta, Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma
  • Organizer: AASLD The Liver Meeting 2019
  • Int'l Joint Research
• [Presentation] C型慢性肝疾患DAA治療後の肝発癌および生命予後の検討 (2019)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: JDDW2019 第23回日本肝臓学会大会