Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

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): Pietro Andreone;Lorenzo Badia;Vanni Borghi;Maria Cristina Cavallo;Luchino Chessa;Valentina Donati;Katia Falasca;Carlo Ferrari;Erika Franceschini;Elisa Garlassi;Giovanni Garrucciu;Dante Giammartino;Alessandro Grimaldi;Valeria Guarneri;Diletta Laccabue;Jacomo Magnani;Giacomo Magnani;Elena Mazzotta;Marianna Menozzi;Gabriele Missale;Cristina Mori;Maria Stella Mura;Cristina Mussini;Andrea Olivani;Maurizio Paoloni;Tarquini Pierluigi;Antonello Pieterangelo;Maria Rosaria Piras;Claudia Pisano;Francesca Prati;Marco Massari;Antonella Sciacca;Maria Pina Sciotti;Monica Tontodonati;Tamara Ursini;Jacopo Vecchiet;Paolo Ventura;Gabriella Verucchi;Gianpaolo Vidili;Teresa Zolfino. HCV Virology Italian Resistance Network (VIRONET-C): Marianna Aragri;Pierluigi Cacciatore;Simona Francioso;Giovanni Battista Gaeta;Vito Di Marco;Chiara Masetti;Filomina Morisco;Valeria Pace Palitti;Alessandro Pieri;Katia Yu La Rosa;Federica Sozio

2021-01-01

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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 these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.