Basic research to achieve precision medicine for hepatocarcinoma occurring in the era of hepatitis virus eradication/suppression.

• Project/Area Number: 19H03638
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Yamanashi
• Principal Investigator: ENOMOTO NOBUYUKI 山梨大学, その他部局等, 理事 (20251530)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 肝炎ウイルス制御後 / 原発性肝癌 / HCV / 次世代シークエンサー / 自然免疫 / ウイルスゲノム / 宿主遺伝子 / HBV / 肝炎制御後肝発癌 / 肝炎ウイルス / 宿主因子 / 次世代シークエンス / バイオマーカー / 肝炎ウイルス制御後肝発癌 / プレシジョンメディシン

Outline of Research at the Start

本研究は”ウイルス制御後肝癌”という新しい病態カテゴリーの特徴をウイルス・宿主分子に着目して統合的に明らかにすることを目的とする。技術的には、病理組織より1細胞を分取可能な高精度レーザーマイクロダイセクション顕微鏡技術とliquid biopsyを含む微量の核酸サンプルからの網羅的遺伝子解析を可能とする次世代シークエンス技術を組み合わせて駆使することにより、これまでにない精度でウイルス制御後肝癌における分子生物学的情報を集積する。また臨床像との関係を明らかとして病態解明・治療効果・予後予測に応用するとともに、新規バイオマーカーの同定・簡便な測定システムの開発を目指してゆく。

Outline of Final Research Achievements

Progression of liver disease or the occurrence of hepatocellular carcinoma (HCC) is still observed in some virus hepatitis patients even after virus elimination with antiviral drugs, and the underlying mechanism is unclear. In this study, using next-generation gene analysis technology, we characterized the information and the dynamics of hepatitis C virus (HCV) genome, HCC genome, and inflammation-related molecules in HCV patients who experienced liver disease advancement or HCC development after viral elimination.

Academic Significance and Societal Importance of the Research Achievements

学術的には、本研究によってウイルス排除後の肝病態進展/発癌に関する肝癌ゲノムの特徴、炎症性サイトカインの動態と病態進展の関連、ハプロタイピングシステムを用いたウイルスゲノムの特徴と病態進展の関連を示すことができた。
また今回構築したhTERT C228T定量リキッドバイオプシーシステムは、正確かつ簡便な肝癌検出および治療反応性の予測が行えるため、直接臨床現場に導入しうる。

Research Products

• [Journal Article] Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing. (2022)
  • Author(s): Yamauchi K, Sato M, Osawa L, Matsuda S, Komiyama Y, Nakakuki N, Takada H, Katoh R, Muraoka M, Suzuki Y, Tatsumi A, Miura M, Takano S, Amemiya F, Fukasawa M, Nakayama Y, Yamaguchi T, Inoue T, Maekawa S, Enomoto N.
  • Journal Title: Hepatol Commun. Volume: -
• [Journal Article] Spontaneous portosystemic shunt diameter predicts liver function after balloon-occluded retrograde transvenous obliteration. (2022)
  • Author(s): Tatsumi A, Maekawa S, Osawa L, Katoh R, Komiyama Y, Nakakuki N, Takada H, Matsuda S, Muraoka M, Suzuki Y, Sato M, Takahashi E, Miura M, Amemiya F, Takano S, Fukasawa M, Yamaguchi T, Nakayama Y, Inoue T, Okada H, Araki T, Onishi H, Enomoto N.
  • Journal Title: JGH Open. Volume: 6(2) Issue: 2 Pages: 139-147
  • DOI: 10.1002/jgh3.12712
• [Journal Article] Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy. (2021)
  • Author(s): Muraoka M, Maekawa S, Katoh R, Komiyama Y, Nakakuki N, Takada H, Matsuda S, Suzuki Y, Sato M, Tatsumi A, Miura M, Amemiya F, Shindo H, Takano S, Fukasawa M, Yamauchi K, Yamaguchi T, Nakayama Y, Inoue T, Enomoto N.
  • Journal Title: Hepatol Commun. Volume: 5(11) Issue: 11 Pages: 1927-1938
  • DOI: 10.1002/hep4.1762
  • Peer Reviewed / Open Access
• [Journal Article] Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy (2021)
  • Author(s): Shuya Matsuda, Shinya Maekawa, Yasuyuki Komiyama, Natsuko Nakakuki, Tatsuya Yamaguchi, Yasuhiro Nakayama, Taisuke Inoue, Tadashi Sato, Atsuya Yamashita, Kohji Moriishi, Nobuyuki Enomoto
  • Journal Title: Hepatology Research Volume: 51 Issue: 1 Pages: 39-50
  • DOI: 10.1111/hepr.13574
  • Peer Reviewed / Open Access
• [Journal Article] Changes of liver stiffness measured by magnetic resonance elastography during direct-acting antivirals treatment in patients with chronic hepatitis C. (2021)
  • Author(s): Higuchi M, Tamaki N, Kurosaki M, Inada K, Kirino S, Yamashita K, Hayakawa Y, Sekiguchi S, Osawa L, Takaura K, Maeyashiki C, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Enomoto N, Izumi N.
  • Journal Title: J Med Virol Volume: 93 Issue: 6 Pages: 3744-3751
  • DOI: 10.1002/jmv.26490
  • Peer Reviewed
• [Journal Article] Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study (2020)
  • Author(s): Tahata Yuki、Hikita Hayato、Matsuura Kentaro、Takehara Tetsuo, et al.
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 1 Pages: 67-77
  • DOI: 10.1007/s00535-020-01733-4
  • Peer Reviewed / Open Access
• [Journal Article] Extravasation and fluid collection on computed tomography imaging in patients with colonic diverticular bleeding. (2020)
  • Author(s): Takada H, Kadokura M, Yasumura T, Yoda H, Okuwaki T, Imagawa N, Shimamura N, Tanaka K, Amemiya F, Enomoto N.
  • Journal Title: PLoS One Volume: 15 Issue: 4 Pages: e0229884-e0229884
  • DOI: 10.1371/journal.pone.0229884
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between presarcopenia and event occurrence in patients with primary hepatocellular carcinoma (2020)
  • Author(s): Takada H, Amemiya F, Yasumura T, Yoda H, Okuwaki T, Imagawa N, Shimamura N, Tanaka K, Kadokura M, Maekawa S, Enomoto N.
  • Journal Title: Sci Rep. Volume: 1 Issue: 1 Pages: 10186-10186
  • DOI: 10.1038/s41598-020-67147-7
  • Peer Reviewed / Open Access
• [Journal Article] Utility of the simplified measurements of muscle mass in patients with gastrointestinal and chronic liver diseases (2020)
  • Author(s): Takada H, Amemiya F, Yasumura T, Yoda H, Okuwaki T, Tanaka K, Kadokura M, Enomoto N.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 10795-10795
  • DOI: 10.1038/s41598-020-67847-0
  • Peer Reviewed / Open Access
• [Journal Article] Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein but not α-fetoprotein as a Long-Term Hepatocellular Carcinoma Predictor. (2020)
  • Author(s): Osawa L, Tamaki N, Kurosaki M, Kirino S, Watakabe K, Wang W, Okada M, Shimizu T, Higuchi M, Takaura K, Takada H, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Enomoto N, Izumi N.
  • Journal Title: Int J Mol Sci Volume: 21 Issue: 10 Pages: 3640-3640
  • DOI: 10.3390/ijms21103640
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-related genetic changes in multistep hepatocarcinogenesis and their correlation with imaging and histological findings (2020)
  • Author(s): Masaru Muraoka, Shinya Maekawa, Yuichiro Suzuki , Mitsuaki Sato, Tatsuya Yamaguchi, Taisuke Inoue, Tadashi Sato, Atsuya Yamashita, Kohji Moriishi, Masanori Matsuda, Nobuyuki Enomoto
  • Journal Title: Hepatology Research Volume: 50 Issue: 9 Pages: 1071-1082
  • DOI: 10.1111/hepr.13529
  • Peer Reviewed / Open Access
• [Journal Article] Twelve weeks of ledipasvir/sofosbuvir all‐oral regimen for patients with chronic hepatitis C genotype 2 infection: Integrated analysis of three clinical trials (2020)
  • Author(s): Asahina Yasuhiro、Liu Chun‐Jen、Gane Edward、Itoh Yoshito、Kawada Norifumi、Ueno Yoshiyuki、Youn Jin、Wang Chen‐Yu、Llewellyn Joe、Matsuda Takuma、Gaggar Anuj、Mo Hongmei、Dvory‐Sobol Hadas、Crans Gerald、Chuang Wan‐Long、Chen Pei‐Jer、Enomoto Nobuyuki
  • Journal Title: Hepatology Research Volume: 50 Issue: 10 Pages: 1109-1117
  • DOI: 10.1111/hepr.13546
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] MRI‐based risk factors of hepatocellular carcinoma in patients with chronic liver disease: A prospective observational study (2019)
  • Author(s): Shimizu Tatsuya、Motosugi Utaroh、Komatsu Nobutoshi、Ichikawa Shintaro、Inoue Taisuke、Onishi Hiroshi、Enomoto Nobuyuki
  • Journal Title: Journal of Magnetic Resonance Imaging Volume: 51 Issue: 2 Pages: 389-396
  • DOI: 10.1002/jmri.26797
  • Peer Reviewed
• [Journal Article] Baseline and Early Predictors of Good Patient Candidates for Second-Line after Sorafenib Treatment in Unresectable Hepatocellular Carcinoma. (2019)
  • Author(s): Takada H, Kurosaki M, Tsuchiya K, Komiyama Y, Itakura J, Takahashi Y, Nakanishi H, Yasui Y, Tamaki N, Maeyashiki C, Kaneko S, Takaura K, Higuchi M, Okada M, Wang W, Osawa L, Sekiguchi S, Hayakawa Y, Yamashita K, Enomoto N, Izumi N
  • Journal Title: Cancers (Basel) Volume: 11(9) Issue: 9 Pages: 1256-1256
  • DOI: 10.3390/cancers11091256
  • Peer Reviewed
• [Journal Article] Wisteria floribunda agglutinin-positive mac-2 binding protein as an age-independent fibrosis marker in nonalcoholic fatty liver disease. (2019)
  • Author(s): Tamaki N, Higuchi M, Kurosaki M, Kirino S, Osawa L, Watakabe K, Wang W, Okada M, Shimizu T, Takaura K, Takada H, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Enomoto N, Izumi N
  • Journal Title: Sci Rep Volume: 9(1) Issue: 1 Pages: 10109-10109
  • DOI: 10.1038/s41598-019-46172-1
  • Peer Reviewed
• [Journal Article] Risk assessment of hepatocellular carcinoma development by magnetic resonance elastography in chronic hepatitis C patients who achieved sustained virological responses by direct-acting antivirals. (2019)
  • Author(s): Tamaki N, Higuchi M, Kurosaki M, Kirino S, Osawa L, Watakabe K, Wang W, Okada M, Shimizu T, Takaura K, Takada H, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Enomoto N, Izumi N
  • Journal Title: J Viral Hepat Volume: 26(7) Issue: 7 Pages: 893-899
  • DOI: 10.1111/jvh.13103
  • Peer Reviewed
• [Journal Article] Sorafenib-Regorafenib Sequential Therapy in Japanese Patients with Unresectable Hepatocellular Carcinoma?Relative Dose Intensity and Post-Regorafenib Therapies in Real World Practice (2019)
  • Author(s): Wang、Tsuchiya、Kurosaki、Yasui、Inada、Kirino、Yamashita、Sekiguchi、Hayakawa、Osawa、Okada、Higuchi、Takaura、Maeyashiki、Kaneko、Tamaki、Nakanishi、Itakura、Takahashi、Asahina、Enomoto、Izumi
  • Journal Title: Cancers Volume: 11 Issue: 10 Pages: 1517-1517
  • DOI: 10.3390/cancers11101517
  • Peer Reviewed
• [Presentation] 非代償性肝硬変・肝癌合併症例におけるHCVウイルスゲノムの検討 (2019)
  • Author(s): 前川 伸哉，松田 秀哉，榎本 信幸
  • Organizer: 第23回 日本肝臓学会大会
• [Presentation] DAA-SVR 後肝発癌，非代償性肝硬変症例における HCV ウイルスゲノムの検討 (2019)
  • Author(s): 前川 伸哉 松田秀哉 榎本信幸
  • Organizer: 第55回 日本肝臓学会総会
• [Presentation] The role of HCV genome and IL28B SNPs in the development of hepatocellular carcinoma after achieving viral elimination following interferon-free therapy. (2019)
  • Author(s): Shinya Maekawa, Shuya Matsuda, Masaru Muraoka, Yuichiro Suzuki, Ryo Katoh, Yasuyuki Komiyama, Natsuko Nakakuki, Akihisa Tatsumi, Yuichiro Suzuki, Yasuhiro Nakayama, Taisuke Inoue, Nobuyuki Enomoto
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] 抗ウイルス治療後の肝発癌におけるウイルスゲノム関与の検討 (2019)
  • Author(s): 前川 伸哉，佐藤 光明，榎本 信幸
  • Organizer: 第105回 日本消化器病学会総会
• [Presentation] DAA による SVR 後の HCC の動向とリスク因子の検討 (2019)
  • Author(s): 佐藤 光明，前川 伸哉，榎本 信幸
  • Organizer: 第105回 日本消化器病学会総会