Abstract 2547: TERT promoter mutations in B viral humanhepatocarcinogenesis

Abstract

Abstract Telomerase reverse transcriptase (TERT) promoter somatic mutations, related to telomerase activation, have been known to frequently occur at two hot spots located at -124 and -146 bp relative to the start codon in various cancers. In the present study, we investigated the occurrence and implications of the genetic alterations of the TERT promoter in B viral hepatocarcinogenesis. TERT promoter mutations, especially -124C>T mutation, obviously enhanced TERT promoter activity in hepatocellular carcinoma (HCC) cell lines. We identified prospero homeobox protein 1 (PROX1) as a novel transcriptional activator for TERT gene through binding to the promoter regions containing two hot spots. PROX1 binding affinity was strong to the mutant TERT promoter harboring a consensus E-twenty six/ ternary complex factor (ETS/TCF) binding sequence (CCGGAA). The incidence of TERT promoter mutations gradually increased according to the progression of human B viral multistep hepaticarcinogenesis, which was found in 9.0% of low grade dysplastic nodules (LGDNs), 13.5% of high grade dysplastic nodules (HGDNs), 27.3% of early HCCs (eHCCs) and 28.4% of progressed HCCs (pHCCs). The occurrence of TERT promoter mutations correlated with lower levels of alpha-fetoprotein (AFP) (p=0.046) and a poor overall survival (p=0.012) in B viral HCC patients. On the contrary to in vitro data, TERT mRNA expression was lower in B viral HCCs with the mutant TERT promoter compared to those without. In addition, mRNA level of PROX1 was not correlated with that of TERT in B viral HCCs, in contrast that such correlation was evident in non-B viral HCCs. Interestingly, induction of stable HBx expression inhibited PROX1-mediated TERT expression in vitro study. In conclusion, our findings suggest that TERT promoter somatic mutations are early events in B viral human multistep hepatocarcinogeneis and HBx can induce a loss of PROX1 function as transcriptional activator for TERT expression. Citation Format: Young-Joo Kim, Jeong Eun Yoo, Youngsic Jeon, Jae Uk Chong, Gi Hong Choi, Dae-Geun Song, Sang Hoon Jung, Bong-Kyeong Oh, Young Nyun Park. TERT promoter mutations in B viral humanhepatocarcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2547.