Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma: e110012

Background 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. This study has investigated the prevalence of...

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Published in:PloS one 2014-10, Vol.9 (10)
Main Authors: Datta, Somenath, Ghosh, Alip, Dasgupta, Debanjali, Ghosh, Amit, Roychoudhury, Shrabasti, Roy, Gaurav, Das, Soumyojit, Das, Kausik, Gupta, Subash, Basu, Keya
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Hepatitis B virus
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container_title PloS one
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creator Datta, Somenath
Ghosh, Alip
Dasgupta, Debanjali
Ghosh, Amit
Roychoudhury, Shrabasti
Roy, Gaurav
Das, Soumyojit
Das, Kausik
Gupta, Subash
Basu, Keya
description Background 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. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naive Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC. Methods The 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. Results Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p less than or equal to 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
doi_str_mv 10.1371/journal.pone.0110012
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This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naive Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC. Methods The 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. Results Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p less than or equal to 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&lt;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. Conclusions Thus 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.</description><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0110012</identifier><language>eng</language><subject>Hepatitis B virus</subject><ispartof>PloS one, 2014-10, Vol.9 (10)</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958,37048</link.rule.ids></links><search><creatorcontrib>Datta, Somenath</creatorcontrib><creatorcontrib>Ghosh, Alip</creatorcontrib><creatorcontrib>Dasgupta, Debanjali</creatorcontrib><creatorcontrib>Ghosh, Amit</creatorcontrib><creatorcontrib>Roychoudhury, Shrabasti</creatorcontrib><creatorcontrib>Roy, Gaurav</creatorcontrib><creatorcontrib>Das, Soumyojit</creatorcontrib><creatorcontrib>Das, Kausik</creatorcontrib><creatorcontrib>Gupta, Subash</creatorcontrib><creatorcontrib>Basu, Keya</creatorcontrib><title>Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma: e110012</title><title>PloS one</title><description>Background 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. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naive Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC. Methods The 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. Results Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p less than or equal to 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&lt;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. 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This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naive Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC. Methods The 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. Results Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p less than or equal to 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&lt;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. Conclusions Thus 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.</abstract><doi>10.1371/journal.pone.0110012</doi></addata></record>
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title Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma: e110012
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