Soo Ki Kim1,2,3, Haruhiko Takeda1,4, Atsushi Takai1, Tomonori Matsumoto1, Nobuyuki Kakiuchi1,2, Akira Yokoyama2, Kenichi Yoshida2, Toshimi Kaido5, Shinji Uemoto5, Sachiko Minamiguchi6, Hironori Haga6, Yuichi Shiraishi7, Satoru Miyano7, Hiroshi Seno1, Seishi Ogawa2, Hiroyuki Marusawa8,9. 1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. 2. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 3. Department of Gastroenterology and Hepatology, Kobe Asahi Hospital, Kobe, Japan. 4. Department of Omics-Based Medicine, Center for Preventive Medicine, Chiba University, Chiba, Japan. 5. Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 6. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. 7. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 8. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. maru@kuhp.kyoto-u.ac.jp. 9. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan. maru@kuhp.kyoto-u.ac.jp.
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.
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.
Entities:
Keywords:
Hepatocarcinogenesis; Liver cirrhosis; TERT; Targeted deep sequencing; Whole-exome sequencing
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