Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

SIMPLE SUMMARY: Telomerase reverse transcriptase (TERT) mutations are the most frequent genetic alterations in hepatocellular carcinoma (HCC). However, integrative analysis studies of TERT-telomere signaling during hepatocarcinogenesis are lacking. In this study, we investigated the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). We found that there are eight key TERT-interacting genes and higher TERT expression and longer telomere length in HCC. We also found TERT-telomeric signals related to correlation with tumor differentiation and stage progression. TERT promoter mutations were an independent predictor of worse overall survival after hepatectomy, while TERT expression independently predicted worse time to progression after TACE. Telomere length was also associated with survival in TACE-treated patients. These findings suggest that TERT-telomere signals might be useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment. ABSTRACT: Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein–protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.