Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis

  • Soo Ki Kim
  • Haruhiko Takeda
  • Atsushi Takai
  • Tomonori Matsumoto
  • Nobuyuki Kakiuchi
  • Akira Yokoyama
  • Kenichi Yoshida
  • Toshimi Kaido
  • Shinji Uemoto
  • Sachiko Minamiguchi
  • Hironori Haga
  • Yuichi Shiraishi
  • Satoru Miyano
  • Hiroshi Seno
  • Seishi Ogawa
  • Hiroyuki MarusawaEmail author
Original Article—Liver, Pancreas, and Biliary Tract



Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing.


We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs.


Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression.


Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.


Hepatocarcinogenesis Liver cirrhosis TERT Targeted deep sequencing Whole-exome sequencing 



We thank Drs. Yoshihide Ueda, Ken Takahashi, Yuji Eso, Tadashi Inuzuka, Tomoyuki Goto, Aya Mizuguchi, Minami Lee, Takahiro Shimizu, Eriko Iguchi, Fumiyasu Nakamura, Soichi Arasawa, Ken Kumagai, Hiromichi Suzuki, and Keisuke Kataoka for interpretation of data and helpful advice. We also thank Drs. Etsuro Hatano, Kojiro Taura, Satoru Seo, and Hideaki Okajima for material support.

Supplementary material

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Copyright information

© Japanese Society of Gastroenterology 2019

Authors and Affiliations

  • Soo Ki Kim
    • 1
    • 2
    • 3
  • Haruhiko Takeda
    • 1
    • 4
  • Atsushi Takai
    • 1
  • Tomonori Matsumoto
    • 1
  • Nobuyuki Kakiuchi
    • 1
    • 2
  • Akira Yokoyama
    • 2
  • Kenichi Yoshida
    • 2
  • Toshimi Kaido
    • 5
  • Shinji Uemoto
    • 5
  • Sachiko Minamiguchi
    • 6
  • Hironori Haga
    • 6
  • Yuichi Shiraishi
    • 7
  • Satoru Miyano
    • 7
  • Hiroshi Seno
    • 1
  • Seishi Ogawa
    • 2
  • Hiroyuki Marusawa
    • 1
    • 8
    Email author
  1. 1.Department of Gastroenterology and Hepatology, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of Pathology and Tumor Biology, Graduate School of MedicineKyoto UniversityKyotoJapan
  3. 3.Department of Gastroenterology and HepatologyKobe Asahi HospitalKobeJapan
  4. 4.Department of Omics-Based Medicine, Center for Preventive MedicineChiba UniversityChibaJapan
  5. 5.Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
  6. 6.Department of Diagnostic PathologyKyoto University HospitalKyotoJapan
  7. 7.Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical ScienceThe University of TokyoTokyoJapan
  8. 8.Department of Gastroenterology and HepatologyOsaka Red Cross HospitalOsakaJapan

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