Abstract
Telomerase activation via induction of the catalytic component telomerase reverse transcriptase (TERT) plays essential roles in malignant transformation. TERT promoter-activating mutations were recently identified as a novel mechanism to activate telomerase in hepatocellular carcinoma (HCC) and many other malignancies. In addition, single nucleotide polymorphisms (SNPs) in the TERT rs2736098 and rs2736100 are significantly associated with cancer susceptibility. It is currently unclear whether different germline TERT variants modify TERT promoter mutations. Here we analyzed the TERT promoter status and genotyped the TERT SNPs at rs2736098 and rs2736100 in patients with HCC. Thirty percent of HCCs harbored TERT promoter mutations and there was a significant difference in rs2736098 and rs2736100 genotypes between wt and mutant TERT promoter-bearing HCC tumors (P = 0.007 and 0.018, respectively). For rs2736100, the cancer risk genotype CC was significantly associated with a reduced incidence of TERT promoter mutations compared to AA + AC variants [Odds ratio (OR): 0.181, 95% Confidence interval (CI): 0.0543–0.601, P = 0.004]. The rs2736098_CT genotype was significantly associated with the TERT promoter mutation-positive tumors compared to the TT genotype (OR: 5.391, 95% CI: 1.234–23.553, P = 0.025). These differences in genotype distribution did not differ between patients with a wt TERT promoter and controls. The presence of TERT promoter mutations was not associated with clinico-pathological variables. Taken together, the germline TERT genetic background may significantly affect the onset of TERT promoter mutations in HCCs, which provides a better understanding of HCC-related TERT promoter mutations and telomerase regulation in cancer.
Highlights
Hepatocellular carcinoma (HCC) is the dominant primary liver cancer with an estimated number of 466,100 new cases and 422,100 deaths, occurring in China for 2015, which is almost the half of all cases diagnosed globally [1]
The germline telomerase reverse transcriptase (TERT) genetic background may significantly affect the onset of TERT promoter mutations in hepatocellular carcinoma (HCC), which provides a better understanding of HCCrelated TERT promoter mutations and telomerase regulation in cancer
Clinic-pathological variables were compared between patients with and without TERT promoter mutations in their tumors, and there were no differences in age, sex, HBV infection, liver cirrhosis, α-fetoprotein levels, tumor sizes, differentiation status and metastasis (Table 1)
Summary
Hepatocellular carcinoma (HCC) is the dominant primary liver cancer with an estimated number of 466,100 new cases and 422,100 deaths, occurring in China for 2015, which is almost the half of all cases diagnosed globally [1]. Significant advances have been made in the understanding of HCC [2, 3]. The etiology and pathogenesis of HCC remains incompletely elucidated [1]. Most HCC patients are diagnosed at an advanced stage, and invasive diseases or distant metastasis accounts for the majority of mortalities due to limited treatment choices [1]. Increased understanding of the HCC pathogenesis, early detection, improved diagnostic and prognostic markers, novel preventive strategies and identification of new therapeutic targets are urgently needed
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