Telomerase reverse transcriptase promoter methylation is related to a risk of recurrence in hepatocellular carcinoma

Abstract

Supported by the Korea Healthcare Technology Research and Development Project of the Ministry of Health and Welfare of the Republic of Korea (HI12C1437). Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the article published in this journal by Nault et al.,1 who observed 0% frequency of somatic mutations in the telomerase reverse transcriptase (TERT) promoter in cirrhotic livers, 6% in low‐grade dysplastic nodules, 19% in high‐grade dysplastic nodules, and 61% in early hepatocellular carcinoma (HCC). These data indicate that TERT promoter mutations are early prognostic markers for HCC, based on their increased frequency in liver carcinogenesis; such an effect was not observed in 10 cancer genes (CTNNB1, TP53, ARID1A, ARID2, NFE2L2, AXIN1, PIK3CA, KEAP1, RPS6KA3, and CDKN2A).1 Nault et al.1 demonstrated that TERT promoter mutations significantly contribute to increased TERT expression in liver carcinogenesis; here, we suggest an additional mechanism regulating TERT expression. Promoter methylation of TERT is observed in various human tumor tissues and transformed cell lines,2 and its hypermethylation is positively associated with TERT expression and poor prognosis in childhood brain tumors.3 Our study of 78 Korean HCC patients reinforces the possibility that TERT promoter methylation is involved in liver carcinogenesis. First, TERT messenger RNA expression was significantly higher in HCC tumor tissues possessing a methylated TERT promoter than in those possessing an unmethylated promoter (Mann‐Whitney test, P < 0.001; Fig. 1A). Second, TERT promoter methylation was associated with poor recurrence‐free survival in HCC patients (log‐rank test, P = 0.026; Fig. 1B) and a significant risk of recurrence, as evidenced by a hazard ratio of 4.612 (95% confidence interval = 1.048‐20.3, P = 0.0432). Because TERT promoter methylation was not associated with somatic mutations at the promoter in HCC tumors (chi‐squared test, P = 0.154), these two factors independently regulate TERT expression. Taken together, these results are consistent with those of previous studies,2 indicating that TERT promoter methylation is positively associated with TERT expression.Figure 1: Methylation at the TERT promoter correlates with high TERT expression and poor recurrence‐free survival rate. (A) The TERT expression level in HCC tumor tissues possessing unmethylated or methylated TERT promoters. Methylation status was checked by methylation‐specific polymerase chain reaction using primer pairs specific for unmethylated or methylated TERT promoters (the region is from 270 bp upstream of the ATG start site to 31 bp upstream of the ATG start site2). Boxes show median, 25th percentile, and 75th percentile, while whiskers show 5th and 95th percentiles. (B) Recurrence‐free survival rates of HCC patients. Recurrence‐free survival rates were estimated using the Kaplan‐Meier method, and the differences in survival rates were compared using the log‐rank test.Findings of this study and that by Nault et al.1 demonstrate that increased TERT expression contributes substantially to HCC progression, suggesting the potential of therapeutic strategies aimed at suppressing TERT expression. Acknowledgment The biospecimens for this study were provided by Seoul St. Mary's Hospital of the Catholic University of Korea and the Korea University Guro Hospital of National Biobank, a member of the National Biobank of Korea.