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Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b

Authors :
Mohammad Alkhatib
Velia Chiara Di Maio
Valentina De Murtas
Ennio Polilli
Martina Milana
Elisabetta Teti
Gianluca Fiorentino
Vincenza Calvaruso
Silvia Barbaliscia
Ada Bertoli
Rossana Scutari
Luca Carioti
Valeria Cento
Maria Mercedes Santoro
Alessandro Orro
Ivana Maida
Ilaria Lenci
Loredana Sarmati
Antonio Craxì
Caterina Pasquazzi
Giustino Parruti
Sergio Babudieri
Luciano Milanesi
Massimo Andreoni
Mario Angelico
Carlo Federico Perno
Francesca Ceccherini-Silberstein
Valentina Svicher
Romina Salpini
on behalf of HIRMA (Hepatocarcinoma Innovative Research MArkers) and Fondazione Vironet C (HCV Virology Italian Resistance
Source :
Viruses, Vol 13, Iss 5, p 743 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

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.

Details

Language :
English
ISSN :
19994915
Volume :
13
Issue :
5
Database :
Directory of Open Access Journals
Journal :
Viruses
Publication Type :
Academic Journal
Accession number :
edsdoj.8259e8118d1f464ca9135d7b58bab389
Document Type :
article
Full Text :
https://doi.org/10.3390/v13050743