Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b.
- Autori: Alkhatib M, Di Maio VC, De Murtas V, Polilli E, Milana M, Teti E, Fiorentino G, Calvaruso V, Barbaliscia S, Bertoli A, Scutari R, Carioti L, Cento V, Santoro MM, Orro A, Maida I, Lenci I, Sarmati L, Craxi A, Pasquazzi C, Parruti G, Babudieri S, Milanesi L, Andreoni M, Angelico M, Perno CF, Ceccherini-Silberstein F, Svicher V, Salpini R, On Behalf Of Hirma Hepatocarcinoma Innovative Research MArkers And Fondazione Vironet C Hcv Virology Italian Resistance.
- Anno di pubblicazione: 2021
- Tipologia: Articolo in rivista
- OA Link: http://hdl.handle.net/10447/519587
Abstract
HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve 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 (5.7-82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4-6.2) log IU/mL vs. 5.3 (4.4-5.6) log IU/mL, p = 0.02) and lower ALT (35 (30-71) vs. 83 (48-108) 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 cell-cycle regulation (p53, p85-PIK3, and β-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 HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.