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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

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.

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Author notes

  1. Soo Ki Kim and Haruhiko Takeda contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Soo Ki Kim, Haruhiko Takeda, Atsushi Takai, Tomonori Matsumoto, Nobuyuki Kakiuchi, Hiroshi Seno & Hiroyuki Marusawa

  2. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Soo Ki Kim, Nobuyuki Kakiuchi, Akira Yokoyama, Kenichi Yoshida & Seishi Ogawa

  3. Department of Gastroenterology and Hepatology, Kobe Asahi Hospital, Kobe, Japan

    Soo Ki Kim

  4. Department of Omics-Based Medicine, Center for Preventive Medicine, Chiba University, Chiba, Japan

    Haruhiko Takeda

  5. Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Toshimi Kaido & Shinji Uemoto

  6. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan

    Sachiko Minamiguchi & Hironori Haga

  7. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yuichi Shiraishi & Satoru Miyano

  8. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan

    Hiroyuki Marusawa

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  1. Soo Ki Kim
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Correspondence to Hiroyuki Marusawa.

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Kim, S.K., Takeda, H., Takai, A. et al. Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis. J Gastroenterol 54, 628–640 (2019). https://doi.org/10.1007/s00535-019-01555-z

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  • DOI: https://doi.org/10.1007/s00535-019-01555-z

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