Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma.

Xunjun Yang,Ping An,Yuning Zhang,Cheryl A Winkler,Qiongya Zhao,Jianxin Lyu,Yao Chen,Guorong Chen,Xiuchan Guo,Kate Huang,Yin Ma

doi:10.18632/oncotarget.8539

Abstract

Telomerase reverse transcriptase (TERT) promoter mutations are among the most frequent noncoding somatic mutations in multiple cancers, including hepatocellular carcinoma (HCC). The clinical and pathological implications of TERT promoter mutations in hepatitis B virus (HBV)-associated HCC have not been resolved. To investigate TERT promoter mutations, protein expression, and their clinical-pathological implications, we sequenced the TERT promoter region for hotspot mutations in HCC tissues and performed immunostaining for TERT protein expression from HBV-associated HCC in Chinese patients. Of 276 HCC tumor DNA samples sequenced, 85 (31%) carried TERT promoter mutations. TERT promoter mutations were more frequent in those with low α-fetoprotein (AFP) serum levels (p = 0.03), advanced age (p = 0.04), and in those lacking HCC family history (p = 0.02), but were not correlated with HCC stages and grades. TERT protein levels were higher in HCC (n = 28) compared to normal liver tissues (n = 8) (p =0.001), but did not differ between mutated and non-mutated tumor tissues. In conclusion, TERT promoter mutations are common somatic mutations in HCC of Han Chinese with HBV infection. Detection of TERT promoter mutations in those with low levels of AFP may aid diagnosis of HCC with atypical presentation.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths in China [1, 2]
We screened for the presence of telomerase promoter mutations in liver tumor tissues from 276 hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients and investigated the clinical relevance of this gain-of-function somatic mutation
We found that 31% of HCC tissue harbored Telomerase reverse transcriptase (TERT) promoter mutations and that the TERT promoter mutations were more often detected in those with low AFP level

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths in China [1, 2]. HCC develops typically in the setting of cirrhosis associated with hepatitis B virus (HBV) infection in China [1, 4, 5]. HCC carcinogenesis involves multiple genetic changes including loss of tumor suppressor genes and activation of oncogenes, while HBV infection caused liver inflammation may induce mutation accumulation in hepatocytes [6]. The precise molecular mechanism of HBV-associated HCC remains unresolved. Telomerase is silent in most normal differentiated cells, while it is activated in up to 90% of human malignancies including HCC, leading to infinite proliferation potential [8,9,10]. The cancerspecific telomerase activation is primarily determined by www.impactjournals.com/oncotarget telomerase reverse transcriptase (TERT) activity, which may be re-activated by epigenetic regulation, TERT amplification or TERT promoter mutations [8, 11, 12]

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Conclusion