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-naive 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 beta-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.

Alkhatib, M., Di Maio, V.C., De Murtas, V., Polilli, E., Milana, M., Teti, E., et al. (2021). Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b. VIRUSES, 13(5), 743 [10.3390/v13050743].

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

Velia Chiara Di Maio;Martina Milana;Elisabetta Teti;Silvia Barbaliscia;Ada Bertoli;Rossana Scutari;Maria Mercedes Santoro;Ilaria Lenci;Loredana Sarmati;Massimo Andreoni;Mario Angelico;Carlo Federico Perno;Francesca Ceccherini-Silberstein;Valentina Svicher;Romina Salpini
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-naive 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 beta-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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/17
eng
NS5A
cirrhosis
genetic variability
genotype 1b
hepatitis C virus
hepatocellular carcinoma
Aged
Biomarkers
Carcinoma, Hepatocellular
Disease Susceptibility
Female
Hepacivirus
Hepatitis C
Host-Pathogen Interactions
Humans
Liver Cirrhosis
Liver Neoplasms
Male
Middle Aged
Mutation
Sequence Analysis, DNA
Severity of Illness Index
Structure-Activity Relationship
Viral Nonstructural Proteins
Genotype
Alkhatib, M., Di Maio, V.C., De Murtas, V., Polilli, E., Milana, M., Teti, E., et al. (2021). Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b. VIRUSES, 13(5), 743 [10.3390/v13050743].
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, M; Orro, A; Maida, I; Lenci, I; Sarmati, L; Craxì, A; Pasquazzi, C; Parruti, G; Babudieri, S; Milanesi, L; Andreoni, M; Angelico, M; Perno, Cf; CECCHERINI SILBERSTEIN, F; Svicher, V; Salpini, R
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/283769
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