Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: characterization and impact on liver disease progression to hepatocellular carcinoma.

Somenath Datta,Analabha Basu,Simanti Datta,Debanjali Dasgupta,Amit Ghosh,Subash Gupta,Keya Basu,Soma Banerjee,Shrabasti Roychoudhury,Alip Ghosh,Abhijit Chowdhury,Gaurav Roy,Soumyojit Das,Kausik Das,Ranjit Ray

doi:10.1371/journal.pone.0110012

Abstract

BackgroundThe contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naïve Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC.MethodsThe mutation profile was determined from the sequence analysis of the full-length HBV genome and compared with the reference HBV sequences. SPSS 16.0 and R software were used to delineate their statistical significance in predicting HCC occurrence.ResultsAge was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p≤0.01). Beyond the classical mutations in basal core promoter (BCP) (A1762T/G1764A) and precore (G1862T), persistence of progressively accumulated mutations in enhancer-I, surface, HBx and core were showed significant association to liver disease progression. BCP_T1753C, core_T147C, surface_L213I had contributed significantly in the disease progression to HCC (p<0.05) in HBeAg positive patients whereas precore_T1858C, core_I116L, core_P130Q and preS1_S98T in HBeAg negative patients. Furthermore, the effect of individual mutation was magnified by the combination with A1762T/G1764A in HCC pathogenesis. Multivariate risk analysis had confirmed that core_P130Q [OR 20.71, 95% CI (1.64–261.77), p = 0.019] in B cell epitope and core_T147C [OR 14.58, 95% CI (1.17–181.76), p = 0.037] in CTL epitope were two independent predictors of HCC in HBeAg positive and negative patients respectively.ConclusionsThus distinct pattern of mutations distributed across the entire HBV genome may be useful in predicting HCC in high-risk CHB patients and pattern of mutational combinations may exert greater impact on HCC risk prediction more accurately than point mutations and hence these predictors may support the existing surveillance strategies in proper management of the patients.

Highlights

Chronic infection with hepatitis B virus (HBV) is the commonest cause of hepatocellular carcinoma (HCC) which is fast emerging as a leading cause of cancer related morbidity and mortality globally [1,2,3]
HCC is the final outcome of chronic hepatitis B (CHB) and liver fibrosis with or without cirrhosis is the hallmark of progressive CHB
It is important to note that HBV has tremendous abilities of immune evasion [5] by either acquiring mutations at viral immune dominant epitopes [6,7] or several critically important sites essential for progressive CHB related to liver diseases [8,9]

Summary

Introduction

Chronic infection with hepatitis B virus (HBV) is the commonest cause of hepatocellular carcinoma (HCC) which is fast emerging as a leading cause of cancer related morbidity and mortality globally [1,2,3]. HCC is the final outcome of CHB and liver fibrosis with or without cirrhosis is the hallmark of progressive CHB. These various clinical outcomes of CHB as a result of complex host–virus immune interplay have a consequential relationship and cirrhosis nearly always precedes HCC development in CHB infection [4]. The contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome.

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