1 research outputs found
Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b
HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domainâ1 interacts with cellular proteins inducing proâoncogenic pathways. Thus, we explore genetic variations in NS5A domainâ1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotypeâ1b infected DAAânaĂŻve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7â82.3); p < 0.001). Focusing on HCCâgroup, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4â6.2) log IU/mL vs. 5.3 (4.4â5.6) log IU/mL, p = 0.02) and lower ALT (35 (30â71) vs. 83 (48â108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cellâcycle regulation (p53, p85âPIK3, and βâ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCVâmediated oncogenesis. The role of these NS5A domainâ1 mutations in triggering proâoncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation