Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

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.

Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma

“…Importantly, our analysis revealed the implications of HBV integration and TERT promoter mutation, which was recently suggested as a potential biomarker in hepatocarcinogenesis [6,15]. We found HBV integration in 84.6% (22/26) of HBV-related tumors, with 38.5% (10/26) containing HBV insertions into the TERT locus.…”

DNA and RNA Binding Proteins: From Motifs to Roles in Cancer

“…TERT activity is minimal in somatic cells, whereas ~90% of human tumors are characterized by telomerase activation [ 250 ] to provide cell immortality. Higher expression is caused mainly by TERT promoter mutations or focal amplification/rearrangements [ 251 ] and is associated with poor survival in many cancer types [ 252 , 253 , 254 , 255 ]. Therapeutic silencing of TERT activity is under evaluation, and several molecules have entered clinical trials [ 256 ].…”

Virus-Driven Carcinogenesis

“…A recent genomic analysis revealed the features of HCC [ 97 , 102 , 103 , 104 ]. The common driver events in HCC are the dysregulation of p53, TERT, and WNT pathways, principally due to mutations in TP53 , the TERT promotor, and CTNNB1, respectively [ 105 , 106 , 107 ]. Consistent with the features of HBV, the majority of HCC cases show genomic integration of HBV [ 97 ].…”