Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma.

Francesca Pezzuto,Fabiana Tatangelo,Luigi Buonaguro,Maria Lina Tornesello,Franco M Buonaguro,Gerardo Botti,Clorinda Annunziata,Francesco Izzo

doi:10.18632/oncotarget.9801

Abstract

Recurrent somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene and in the exon 3 of CTNNB1 gene have been recognized as common events in hepatocellular carcinoma (HCC) with variable frequencies depending on etiology and geographical region. We have analyzed TERT promoter and CTNNB1 gene mutations in 122 cases of hepatitis B (HBV) and hepatitis C (HCV) related HCCs, in 7 cases of cholangiocarcinoma (CC) and hepatocholangiocarcinoma (HCC-CC) as well as in autologous cirrhotic tissues. Overall, 50.4% and 26% of HCC as well as 14.3% and none of CC and HCC-CC were mutated in TERT promoter and in CTNNB1 exon 3, respectively. TERT and CTNNB1 mutations were found more frequently in HCV related (53.6% and 26.4%, respectively) than HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in 57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1 were not associated with the functional promoter polymorphism rs2853669. No mutations were detected in the 129 non-HCC cirrhotic tissues. In conclusion, mutations in TERT promoter and in CTNNB1 gene represent specific cancer signatures in the pathogenesis of viral related HCC and could be promising early biomarkers as well as targets for tailored therapies.

Highlights

Primary liver cancer is the sixth most common tumor in the world with 782,000 new cases and 746,000 deaths in 2012, of which above 80% occur in less developed countries [1]
We evaluated genotype distribution of telomerase reverse transcriptase (TERT) rs2853669 polymorphism and the frequency of somatic mutations in TERT promoter and in exon 3 of β-catenin 1 (CTNNB1) gene in a series of hepatitis C virus (HCV)- and HBVpositive cases diagnosed with Hepatocellular carcinoma (HCC) or CC/HCC-CC, along with autologous non-tumor tissue, from people living in Southern Italy, a geographic area with a very high incidence of liver cancer
TERT promoter mutations were absent in the three HCCCC and in 5 non-viral HCC tested in this study

Summary

Introduction

Primary liver cancer is the sixth most common tumor in the world with 782,000 new cases and 746,000 deaths in 2012, of which above 80% occur in less developed countries [1]. In Europe the highest incidence has been reported in Southern regions (age standardized rate [ASR] = 7.1 per 100,000 population in Italy) and the lowest in the Northern (ASR = 1.7 cases per 100,000 population in Iceland) [1]. Hepatocellular carcinoma (HCC), arising from hepatocytes, represents the dominant histotype of primary liver cancer accounting for 70%-85% of all cases worldwide [3]. Hepatitis B (HBV) and hepatitis C (HCV) infections represent the major risk factors for HCC being associated with more than 80% of liver cancer cases worldwide [7]. In Southern Italy 23.2% of men aged 65 years or older are HCV-positive [11] and over 60% of HCC cases develop on cirrhosis caused by chronic HCV infection [12]

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