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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancerrelated death worldwide
TERT promoter mutations were significantly more common in HCCs related to hepatitis C virus (HCV) infection (5/6; 83.3%) compared to tumors of other etiologies (P = 0.001)
We evaluated the frequency of TERT promoter and CTNNB1 mutations in 146 hepatocellular nodules including hepatocellular adenomas (HCAs), large regenerating nodules (LRNs), low grade dysplastic nodules (LDNs), high-grade dysplastic nodules (HDNs), HCCs, and combined HCCs and cholangiocarcinomas
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancerrelated death worldwide. The recurrence of HCC after resection remains the major cause of death [1, 2]. The majority of HCCs develop in liver cirrhosis related to chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, alcohol intake, and obesity. HCC is considered to develop in a multistep process, in which a precursor or premalignant lesion progresses to dysplastic nodules, followed by HCC. Hepatocarcinogenesis has been characterized as the progressive accumulation of a variety of genetic alterations in chronic liver disease. It is well known that HCCs are phenotypically and genetically heterogeneous tumors. A detailed understanding of the genomic alterations in HCC can improve tumor characterization to help identify www.impactjournals.com/oncotarget
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