Human Telomerase Reverse Transcriptase Gene Promoter Mutation in Serum of Patients with Hepatocellular Carcinoma

Abstract

Background: Mutations in the human telomerase reverse transcriptase (hTERT) gene promoter have been reported in hepatocellular carcinoma (HCC); however, analyses of these mutations in liquid biopsies have been technically difficult because of the high GC content of the regions of interest within this promoter. We evaluated the feasibility and prognostic value of hTERT promoter mutations identified in circulating cell-free DNA (cfDNA) from the serum of patients with HCC. Objective: A cohort of HCC patients (n = 36) who were curatively treated by surgical resection between June 2003 and September 2014 were enrolled in this study. Methods: The presence of hTERT promoter mutations in cfDNA from the patients' serum was analyzed via modified droplet digital polymerase chain reaction, and associations were sought between specific promoter mutations and patients' diseasefree survival (DFS). Results: The G>A hTERT mutation at -124 bp was detected in the serum of 25 patients (69%). Although no marked differences were observed between the characteristics of the serum mutation-positive and serum mutation-negative patient groups, the DFS of patients with the mutation was significantly shorter than that of the serum mutation-negative patients (p = 0.02). Among 18 clinicopathologic and background liver factors examined, the presence of the -124 bp G>A mutation was an independent and significant predictor of patients' DFS (hazard ratio = 3.01, 95% confidence interval 1.11-10.5, p = 0.03) in multivariate analyses. Conclusions: The -124 bp G>A hTERT promoter mutation was observed in the serum of 69% of HCC patients who underwent surgical resection and was an independent predictor of disease progression in HCC.

TERT Promoter Mutation in Serum Cell-Free DNA Is a Diagnostic Marker of Primary Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease

“…The present study on HCC patients with NAFLD background indicated that TERT C228T neither influenced the cumulative liver-related survival rate nor the HCC recurrence rate. The reasons for the difference between our results and those of Ako et al [22] may be related to differences in the etiology and the number of patients who underwent surgical resection. Further studies on large numbers of HCC patients of similar etiology should be performed to determine the true impact of TERT promoter mutation on disease progression.…”

“…Admittedly, we must interpret the present findings with caution, due to the low sensitivity of our method using WTB-PCR compared with that reported in previous studies using droplet digital PCR [21, 22]. New WTB-PCR-based highly sensitive methods for the detection of TERT promoter mutation should be developed in the future.…”

“…As prognostic factors in HCC patients with NAFLD background, serum albumin level and curative treatment for HCC have been reported [26]; however, the impact of TERT C228T is still unclear. Ako et al [22] have recently reported that TERT C228T was an independent predictor of disease progression mainly in HCC patients with viral etiology, who underwent surgical resection [22]. However, to our knowledge, there is still no information on the effects of TERT promoter mutation on liver-related survival rate and HCC recurrence rate in NAFLD patients.…”

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

“…Abnormalities in TERT expression or promoter mutations in HCC have been sporadically studied and reported to be associated with cancer recurrence and progression [ 10 , 11 , 12 , 13 , 14 ]. However, the clinical implications and molecular mechanisms underlying HCC initiation and progression are still unclear because only limited studies have been conducted and the previous studies included only a small number of patients or were limited only to the surgical setting of early-stage HCC.…”

Significance of cytoplasmic expression of telomerase reverse transcriptase in patients with hepatocellular carcinoma undergoing liver resection

“…Because the TERT mutation already occurs in premalignant liver tumor cells ( 9 , 12 ), the role of TERT in HCC probably does not involve tumor progression, but rather involves liver carcinogenesis and tumor dedifferentiation. Recently, Ako et al ( 32 ) evaluated the human TERT promotor mutations detected in the serum of the HCC patients using modified droplet digital polymerase chain reaction and found that positive TERT promotor mutation was significantly associated with shorter recurrence-free survival period after surgery. Clinical impact of TERT gene promotor mutation as well as overexpression of TERT protein on tumor biology and patient outcomes is to be clarified by various aspects of investigations.…”