title: TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma.
abstract: The number of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD-related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD-HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD-HCC tumor samples from these 10 patients by whole-exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole-exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD-HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole-exome sequencing and 14 representative HCC-associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array-based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD-HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD-HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD-related liver carcinogenesis.
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Soo
authors: S
authors: Ki Kim
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Yoshihide
authors: Y
authors: Ueda
authors: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Etsuro
authors: E
authors: Hatano
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Nobuyuki
authors: N
authors: Kakiuchi
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Haruhiko
authors: H
authors: Takeda
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Tomoyuki
authors: T
authors: Goto
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Takahiro
authors: T
authors: Shimizu
authors: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kenichi
authors: K
authors: Yoshida
authors: Department of Pathology, Takatsuki General Hospital, Osaka, Japan.
authors: Yoshihiro
authors: Y
authors: Ikura
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Yuichi
authors: Y
authors: Shiraishi
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Kenichi
authors: K
authors: Chiba
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Hiroko
authors: H
authors: Tanaka
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Satoru
authors: S
authors: Miyano
authors: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Shinji
authors: S
authors: Uemoto
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Tsutomu
authors: T
authors: Chiba
authors: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Seishi
authors: S
authors: Ogawa
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. maru@kuhp.kyoto-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Marusawa
mesh_terms: D000368:Aged; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: TERT promoter mutation; genetic aberrations; hepatocellular carcinoma; liver carcinogenesis; nonalcoholic fatty liver disease