title: Frequent somatic TERT promoter mutations and CTNNB1 mutations in hepatocellular carcinoma.
abstract: Genetic alterations of TERT and CTNNB1 have been documented in hepatocellular carcinoma. TERT promoter mutations are the earliest genetic events in the multistep process of hepatocarcinogenesis related to cirrhosis. However, analyses of TERT promoter and CTNNB1 mutations in hepatocellular carcinoma tumor samples have not been performed in the Korean population, where hepatitis B virus-related hepatocellular carcinoma is prevalent. In order to identify the role of TERT promoter and CTNNB1 mutations in the hepatocarcinogenesis and pathogenesis of recurrent hepatocellular carcinoma, we performed the sequence analyses in 140 hepatocellular nodules (including 107 hepatocellular carcinomas), and 8 pairs of matched primary and relapsed hepatocellular carcinomas. TERT promoter and CTNNB1 mutations were only observed in hepatocellular carcinomas but not in precursor lesions. Of 109 patients with hepatocellular carcinoma, 41 (39.0%) and 15 (14.6%) harbored TERT and CTNNB1 mutations, respectively. TERT promotermutations were significantly more frequent in hepatocellular carcinomas related to hepatitis C virus infection (5/6; 83.3%) compared to tumors of other etiologies (P = 0.001). In two cases, discordance in TERT promoter mutation status was observed between the primary and the corresponding recurrent hepatocellular carcinoma. The two patients with discordant cases had early relapses. In conclusion, we identified TERT promoter and CTNNB1 mutations as the most frequent somatic genetic alterations observed in hepatocellular carcinoma, indicating its pivotal role in hepatocarcinogenesis. Furthermore, we suggest the possibility of intratumoral genetic heterogeneity of TERT promoter mutations in hepatocellular carcinoma as indicated by the discordance in TERT promoter mutations between primary and corresponding recurrent hepatocellular carcinoma.
authors.affiliation: Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Seung Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Surgery, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Wook Youn
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: So Dug
authors.initials: SD
authors.lastname: Lim
authors.affiliation: Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Wan Seop
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Tea Sook
authors.initials: TS
authors.lastname: Hwang
authors.affiliation: Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Han
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D056910:Republic of Korea; D019098:Telomerase / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D019098:Telomerase
keywords: CTNNB1; Pathology Section; TERT; hepatocellular carcinoma; intratumoral genetic heterogeneity