2017 Fiscal Year Annual Research Report
発癌・進展に関わる背景肝ゲノム要因の探索とiPS細胞を用いた肝発癌機構の統合解析
| Project/Area Number |
16H05285
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
朝比奈 靖浩 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692)
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| Co-Investigator(Kenkyū-buntansha) |
柿沼 晴 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (30372444)
中川 美奈 東京医科歯科大学, 統合教育機構, 准教授 (30401342)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 肝癌 / HBV / HCV / HBV integration |
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| Outline of Annual Research Achievements |
申請者らはウイルス排除後にも依然発癌リスクが存在することを明らかとしてきた(Hepatology 2010, 2013)。本年度は、半導体シークエンサーを用いて肝細胞癌関連遺伝子プロファイルを網羅的に解析し、HCV排除（SVR）の有無および核酸アナログ(NUCs)によるHBV複製制御の有無による発癌要因の差異について検討した。対象は肝切除をした142例。癌部と背景肝において癌関連54遺伝子2910箇所のhotspotに対してdeep sequenceを施行し、TERT promoter領域のhotspotについては direct sequenceとdeep sequenceを行った。また、HBs抗原陽性例においてはHBV integrationをIllumina Miseqを用いて網羅的に解析した。C型肝癌ではTERT promoter変異84%, CTNNB1変異61%, TP53変異28%とTP53 変異は少ないが (p = 0.002)、TERT promoter変異が多く (p = 0.003)、SVRの有無による遺伝子変異の頻度に差は認めなかった。B型肝癌ではTP53変異 67.9%, TERT promoter変異 30%, CTNNB1変異 11%で遺伝子変異を認め、HBV integrationを93%に検出しヒト側ではTERT、MLL4、MYO7A が多かった。NUCs内服の有無でHBV integrationの頻度に差はなかったがTERT promoter変異はNUCs内服群で内服していない群と比較して低下しており、HBV DNA検出感度未満の症例で有意に少なかった(p = 0.02)。これらの解析結果から、C型肝炎ではウイルス排除の有無で遺伝子変異による発癌機序の違いは明らかではなかったが、B型肝炎ではHBV複製制御の有無で異なることが示唆された。
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
本年度は、HCV排除の有無および核酸アナログ薬によるHBV複製制御の有無による癌遺伝子プロファイルの差異に関して、高頻度に変異がみられる遺伝子について検討することができた。しかし、変異が低頻度の遺伝子の解析や結果の検証のためには更なる症例の集積と解析が必要である。
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| Strategy for Future Research Activity |
HCV排除後やHBV制御下の発癌に関与する遺伝要因を解明するために、症例を集積して更なる解析を行う。今回、B型肝癌の発癌にHBV integrationが大きく関与することが明らかとなったことから、更にHBVゲノムと宿主ゲノムの相互作用と発癌機構を解明するために、HBs抗原持続陽性例に加えHBV既往感染からの発癌例を対象として、HBV-宿主遺伝子の関連を解析する。また、これらの検討からin vitroにおける発癌機構を解明するために必要なHBV-宿主キメラ遺伝子等の基盤情報を得る。本研究ではこれらを統合的に推進することで肝発癌機構の全容解明に関わる知的・技術的基盤の確立を目指す。
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[Journal Article] Ledipasvir-sofosbuvir for treating Japanese patients with chronic hepatitis C virus genotype 2 infection.2018
Author(s)
Asahina Y, Itoh Y, Ueno Y, Matsuzaki Y, Takikawa Y, Yatsuhashi H, Genda T, Ikeda F, Matsuda T, Dvory-Sobol H, Jiang D, Massetto B, Osinusi AO, Brainard DM, McHutchison JG, Kawada N, Enomoto N.
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Journal Title
Liver Int
Volume: 印刷中
Pages: 印刷中
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Up-to-seven criteria as a useful predictor for tumor downstaging to within Milan criteria and Child-Pugh grade deterioration after the initial conventional TACE.2017
Author(s)
Yasui Y, Tsuchiya K, Kurosaki M, Takeguchi T, Takeguchi Y, Okada M, Wang W, Kubota Y, Goto T, Komiyama Y, Higuchi M, Takaura K, Hayashi T, Takada H, Tamaki N, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Enomoto N, Himeno Y, Izumi N.
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Journal Title
Hepatol Res
Volume: 印刷中
Pages: 印刷中
DOI
Peer Reviewed
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[Journal Article] Association Between Alanine Aminotransferase Elevation And UGT1A1*6 Polymorphisms In Daclatasvir And Asunaprevir Combination Therapy For Chronic Hepatitis C.2017
Author(s)
Maekawa S, Sato M, Kuratomi N, Inoue T, Suzuki Y, Tatsumi A, Miura M, Matsuda S, Muraoka M, Nakakuki N, Amemiya F, Takano S, Fukasawa M, Nakayama Y, Yamaguchi T, Sato T, Sakamoto M, Murakawa M, Nakagawa M, Asahina Y, Enomoto N.
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Journal Title
J Gastroenterol
Volume: 印刷中
Pages: 印刷中
DOI
Peer Reviewed
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[Journal Article] Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.2017
Author(s)
Nagata H, Nakagawa M, Asahina Y＊, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M, and the Ochanomizu Liver Conference Study Group.
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Journal Title
J Hepatol
Volume: 67
Pages: 933-939
DOI
Peer Reviewed
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[Journal Article] Hepatic IFNL4 expression is associated with non-response to interferon-based therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients.2017
Author(s)
Murakawa M, Asahina Y＊§, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano A, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda T, and Watanabe M.
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Journal Title
J Med Virol
Volume: 89
Pages: 1241-1247
DOI
Peer Reviewed
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[Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin.2017
Author(s)
Murakawa M§, Asahina Y＊§, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
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Journal Title
Hepatol Res
Volume: 47
Pages: 1212-1218
DOI
Peer Reviewed
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[Journal Article] Hepatitis B Surface Antigen Reduction by Switching from Long-term Nucleoside/nucleotide Analog Administration to Pegylated Interferon.2017
Author(s)
Tamaki N, Kurosaki M, Kusakabe A, Orito E, Joko K, Kojima Y, Kimura H, Uchida Y, Hasebe C, Asahina Y, Izumi N.
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Journal Title
J Viral Hepat
Volume: 24
Pages: 672-678
DOI
Peer Reviewed
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[Journal Article] Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells.2017
Author(s)
Goto F, Kakinuma S, Miyoshi M, Tsunoda T, Kaneko S, Sato A, Asano Y, Otani S, Azuma S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Asahina Y, Watanabe M.
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Journal Title
Hepatol Res
Volume: 47
Pages: 941-952
DOI
Peer Reviewed
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[Presentation] Twelve Weeks of Ledipasvir/Sofosbuvir All-oral Regimen for Patients with Chronic Hepatitis C Genotype 2 Infection: Integrated Analysis of Three Clinical Studies.2018
Author(s)
Asahina Y, Liu CJ, Gane E, Itoh Y, Kawada N, Ueno Y, Wang CY, Llewellyn J, Osinusi A, Svarovskaia J, Mo H, Crans G, Chuang WL, Chen PJ, Enomoto N.
Organizer
27th conference of the Asian Pacific Association for the Study of the Liver (APASL 2018)
Int'l Joint Research
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[Presentation] Novel culture model for coinfection of hepatitis B and hepatitis C viruses using human induced pluripotent stem cell-derived hepatic cells for analyses of changes in host-innate immune responses.2017
Author(s)
Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Nitta S, Sato A, Asano Y, Nagata H, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Watanabe M.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] Evaluation of an early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C patients treated with DAAs - Retrospective review of a prospective database -.2017
Author(s)
Nakagawa M, Asahina Y, Nagata H, Sato A, Miyoshi M, Tsunoda T, Asano Y, Kaneko S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Watanabe M.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017),
Int'l Joint Research
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[Presentation] The analysis of NS5A Resistance-Associated Substitutions (RAS): In vitro study of NS5A recombinant hepatitis C in infectious cell culture system for various RAS detected after treatment failure in chronic hepatitis C patients.2017
Author(s)
Nitta S, Murakawa M, Kato T, Sato A, Tsunoda T, Miyoshi M, Asano Y, Kaneko S, Nagata H, Kawai-Kitahata F, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Asahina Y.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] On-treatment higher levels of alpha-fetoprotein and M2BPGi are associated with development of hepatocellular carcinoma during nucleos(t)ide analog therapy in patients with HBV chronic infection.2017
Author(s)
Murakawa M, Asahina Y, Nakagawa M, Sato A, Miyoshi M, Tsunoda T, Asano Y, Nagata H, Kaneko S, Kawai-Kitahata F, Nitta S, Itsui Y, Azuma S, Kakinuma S, Watanabe M.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] Ledipasvir/Sofosbuvir in the Treatment of Japanese Patients with Chronic HCV Genotype 2 Infection.2017
Author(s)
Asahina Y, Itoh Y, Ueno Y, Matsuzaki Y, Takikawa Y, Yatsuhashi H, Genda T, Ikeda F, Matsuda T, Jiang D, Huang KC, Massetto B, Osinusi A, Brainard DM, McHutchison JG, Kawada N, Enomoto N.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] Genetic differences in hepatocellular carcinoma among chronic persistent hepatitis B virus (HBV) infection with or without viral suppression and prior HBV infection.2017
Author(s)
Asahina Y, Tanaka S, Kakinuma S, Murakawa M, Nitta S, Watanabe T, Otani S, Goto F, Nagata H, Kaneko S, Azuma S, Itsui Y, Nakagawa M, Tanabe M, Maekawa S, Enomoto N, Watanabe M.
Organizer
The 52th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2017)
Int'l Joint Research
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[Presentation] 慢性肝疾患の線維化発がん阻止への展望 ヒトiPS細胞由来肝臓系譜細胞による病態モデルの作成と先天性肝線維症の病態解析.2017
Author(s)
角田知之, 柿沼 晴, 三好正人, 佐藤綾子, 四宮恵美, 金子 俊, 浅野 侑, 村川美也子, 新田沙由梨, 井津井康浩, 東 正新, 中川美奈, 朝比奈靖浩, 渡辺 守.
Organizer
第54回日本消化器免疫学会総会
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