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

Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b / Alkhatib, Mohammad; Chiara Di Maio, Velia; DE MURTAS, Valentina; Polilli, Ennio; Milana, Martina; Teti, Elisabetta; Fiorentino, Gianluca; Calvaruso, Vincenza; Barbaliscia, Silvia; Bertoli, Ada; Scutari, Rossana; Carioti, Luca; Cento, Valeria; Mercedes Santoro, Maria; Orro, Alessandro; Maida, Ivana; Lenci, Ilaria; Sarmati, Loredana; Craxì, Antonio; Pasquazzi, Caterina; Parruti, Giustino; Babudieri, Sergio; Milanesi, Luciano; 5, Massimo Andreoni; Angelico, Mario; Federico Perno, Carlo; Ceccherini-Silberstein, Francesca; Svicher, Valentina; Salpini, Romina. - In: VIRUSES. - ISSN 1999-4915. - (2021). [10.3390/v13050743]

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

Valentina De Murtas;Ivana Maida
;
Sergio Babudieri;
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
Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b / Alkhatib, Mohammad; Chiara Di Maio, Velia; DE MURTAS, Valentina; Polilli, Ennio; Milana, Martina; Teti, Elisabetta; Fiorentino, Gianluca; Calvaruso, Vincenza; Barbaliscia, Silvia; Bertoli, Ada; Scutari, Rossana; Carioti, Luca; Cento, Valeria; Mercedes Santoro, Maria; Orro, Alessandro; Maida, Ivana; Lenci, Ilaria; Sarmati, Loredana; Craxì, Antonio; Pasquazzi, Caterina; Parruti, Giustino; Babudieri, Sergio; Milanesi, Luciano; 5, Massimo Andreoni; Angelico, Mario; Federico Perno, Carlo; Ceccherini-Silberstein, Francesca; Svicher, Valentina; Salpini, Romina. - In: VIRUSES. - ISSN 1999-4915. - (2021). [10.3390/v13050743]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/246684
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact