Prediction of the risk of non-viral hepatocarcinogenesis by machine learning using genomic information of host and intestinal commensal bacteria

• Project/Area Number: 20K08288
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hiroshima University
• Principal Investigator: Miki Daiki 広島大学, 医系科学研究科(医), 講師 (10584592)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヒトゲノム / 腸内細菌 / 非ウイルス性肝癌 / 機械学習 / 肝癌 / NASH / NAFLD / ゲノム / 遺伝子多型

Outline of Research at the Start

非アルコール性脂肪肝炎（NASH）などに起因する非ウイルス性の肝癌が増加傾向である。糖尿病や肥満の他、宿主の遺伝的要因などにより、リスク群の囲い込みが図られているが、まだ十分とは言えない。一方で、腸内細菌叢（腸内フローラ）が糖尿病や肥満、さらには肝疾患を含めた種々の疾患に関わることが明らかになってきた。腸内細菌叢は、食習慣に大きな影響を受け、加齢により変化し、遺伝的要因との関連も示唆されている。ヒトおよび腸内細菌のゲノム情報を機械学習の手法によって統合的に解析することで、非ウイルス性肝発癌リスク因子の抽出を目指す。

Outline of Final Research Achievements

Non-viral liver cancers are on the rise. One of the causes is the increase in non-alcoholic steatohepatitis (NASH). On the other hand, it has become clear that the gut microbiota is involved in various diseases including diabetes, obesity, and even liver diseases. In this study, we aimed to extract non-viral hepatocarcinogenic risk factors by integrating the human genome, its transcripts, and the genomes of commensal microorganisms, i.e., intestinal bacteria, using machine learning methods. As a result, we were able to construct several models for predicting hepatocarcinogenesis. We plan to prospectively confirm the prediction accuracy of each model.

Academic Significance and Societal Importance of the Research Achievements

これまで経験を積み上げてきたヒトゲノムあるいはがんゲノムやトランスクリプト研究といった特徴的な基盤の上に、さらにメタゲノムという共生する非宿主生物由来の新たな情報を加えることで、独自のアプローチで非ウイルス性肝癌のリスク因子に迫ることを目指す。食生活の変化を含めた環境要因などの外的要因がリスクを高めるとも推測されるが、それに影響をうけて可逆的に変化をするメタゲノム情報と、一生変わることなく安定なヒトゲノム情報とを網羅的に統合解析するのは、新たな手法である。これまでの単階層解析では見えてこなかった未知の特徴量の抽出を行い、より有用な疾患リスク評価を行うことで、これら疾患群の診療への貢献を目指す。

Research Products

• [Journal Article] Increasing incidence of non-HBV- and non-HCV-related hepatocellular carcinoma: single-institution 20-year study. (2021)
  • Author(s): Nagaoki Y, Hyogo H, Ando Y, Kosaka Y, Uchikawa S, Nishida Y, Teraoka Y, Morio K, Fujino H, Ono A, Nakahara T, Murakami E, Yamauchi M, Okamoto W, Kawaoka T, Tsuge M, Hiramatsu A, Miki D, Imamura M, Takahashi S, Chayama K, Aikata H.
  • Journal Title: BMC Gastroenterol. Volume: 21(1) Issue: 1 Pages: 306-306
  • DOI: 10.1186/s12876-021-01884-5
  • Peer Reviewed / Open Access
• [Journal Article] 肝炎ウイルス排除後の肝発がん (2021)
  • Author(s): 三木大樹、相方浩、茶山一彰
  • Journal Title: 月刊薬事 Volume: 63(4) Pages: 77-82
• [Journal Article] In vitro analysis of hepatic stellate cell activation influenced by transmembrane 6 superfamily 2 polymorphism. (2021)
  • Author(s): Liu S, Murakami E, Nakahara T, Ohya K, Teraoka Y, Makokha GN, Uchida T, Morio K, Fujino H, Ono A, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Abe-Chayama H, Hayes NC, Imamura M, Aikata H, Chayama K.
  • Journal Title: Mol Med Rep. Volume: 23(16) Issue: 1 Pages: 1-7
  • DOI: 10.3892/mmr.2020.11654
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of liver disease state progression in patients with eradication of versus persistent infection with hepatitis C virus: Markov chain analysis. (2021)
  • Author(s): Tada T, Toyoda H, Kumada T, Kurisu A, Sugiyama A, Akita T, Ohisa M, Aikata H, Miki D, Chayama K, Tanaka J.
  • Journal Title: J Viral Hepat. Volume: 28(3) Issue: 3 Pages: 538-547
  • DOI: 10.1111/jvh.13444
  • Peer Reviewed
• [Journal Article] C型肝炎による発癌のリスク因子 (2020)
  • Author(s): 三木大樹、茶山一彰
  • Journal Title: 消化器内科 Volume: 2(5) Pages: 76-82
• [Journal Article] Risk factors for histological progression of non-alcoholic steatohepatitis analyzed from repeated biopsy cases. (2020)
  • Author(s): Daijo K, Nakahara T, Inagaki Y, Nanba M, Nishida Y, Uchikawa S, Kodama K, Oya K, Morio K, Fujino H, Ono A, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Hayes CN, Imamura M, Aikata H, Ochi H, Chayama K.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 8 Pages: 1412-1419
  • DOI: 10.1111/jgh.14968
  • Peer Reviewed / Open Access
• [Journal Article] Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases (2020)
  • Author(s): Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Yamaji T, et al
  • Journal Title: Nature Genetics Volume: 52 Issue: 7 Pages: 669-679
  • DOI: 10.1038/s41588-020-0640-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PD1 gene polymorphism is associated with a poor prognosis in hepatocellular carcinoma following liver resection, cohort study. (2020)
  • Author(s): Yamamoto M, Kobayashi T, Mashima H, Miki D, Kuroda S, Hamaoka M, Aikata H, Chayama K, Ohdan H.
  • Journal Title: Int J Surg. Volume: 80 Pages: 84-90
  • DOI: 10.1016/j.ijsu.2020.05.007
  • NAID: 120007168956
  • Peer Reviewed
• [Journal Article] Impact of viral eradication by direct-acting antivirals on the risk of hepatocellular carcinoma development, prognosis, and portal hypertension in hepatitis C virus-related compensated cirrhosis patients. (2020)
  • Author(s): Nagaoki Y, Imamura M, Teraoka Y, Morio K, Fujino H, Ono A, Nakahara T, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Hayes CN, Chayama K, Aikata H.
  • Journal Title: Hepatol Res. Volume: 50(11) Issue: 11 Pages: 1222-1233
  • DOI: 10.1111/hepr.13554
  • Peer Reviewed
• [Journal Article] PNPLA3 and HLA-DQB1 polymorphisms are associated with hepatocellular carcinoma after hepatitis C virus eradication. (2020)
  • Author(s): Miki D, Akita T, Kurisu A, Kawaoka T, Nakajima T, Hige S, Karino Y, Toyoda H, Kumada T, Tsuge M, Hiramatsu A, Imamura M, Aikata H, Hayes CN, Honda K, Seike M, Akuta N, Kobayashi M, Kumada H, Tanaka J, Chayama K.
  • Journal Title: J Gastroenterol. Volume: 55(12) Issue: 12 Pages: 1162-1170
  • DOI: 10.1007/s00535-020-01731-6
  • Peer Reviewed
• [Presentation] SVR後新規肝発癌リスク層別化における経時的AFP変化の意義 (2021)
  • Author(s): 三木大樹，田中純子，茶山一彰
  • Organizer: 第29回日本消化器関連学会週間
• [Presentation] SVR後の肝発癌リスク予測に有用な血清AFP値に関する検討 (2021)
  • Author(s): 三木大樹、相方浩、藤野初江、大野敦司、山内理海、柘植雅貴、茶山一彰
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] C型肝炎ウイルス排除後の新規肝発癌とPNPLA3遺伝子多型の検討 (2021)
  • Author(s): 三木大樹、田中純子、茶山一彰
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] C型肝炎ウイルス排除後の新規肝発癌に関わるリスク因子の検討 (2020)
  • Author(s): 三木大樹、田中純子、茶山一彰
  • Organizer: 第28回日本消化器関連学会週間
• [Presentation] PNPLA3遺伝子多型はHCV排除後の肝発癌に関連する (2020)
  • Author(s): 三木大樹, 相方浩、藤野初江、大野敦司、山内理海、柘植雅貴、茶山一彰
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 肝疾患における病因特異的な腸内細菌叢パターンの探索 (2020)
  • Author(s): 三木大樹, 河岡友和、茶山一彰
  • Organizer: 第106回日本消化器病学会総会
• [Book] 消化器・肝臓内科 第10巻第6号「SVR後肝発癌と遺伝子多型」 (2021)
  • Author(s): 三木大樹、茶山一彰
  • Total Pages: 6
  • Publisher: 科学評論社