Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b
| Autor: | 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. |
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| Přispěvatelé: | 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. |
| Rok vydání: | 2021 |
| Předmět: |
hepatitis C virus
Liver Cirrhosis Male Cirrhosis viruses Hepacivirus Viral Nonstructural Proteins NS5A medicine.disease_cause Severity of Illness Index genetic variability Medicine Liver Neoplasms virus diseases hepatocellular carcinoma Middle Aged Hepatitis C QR1-502 Infectious Diseases Hepatocellular carcinoma HCV Host-Pathogen Interactions Female Disease Susceptibility Carcinoma Hepatocellular Genotype Hepatitis C virus Viremia Microbiology Article Structure-Activity Relationship Virology Genetic variation Humans Genetic variability neoplasms Aged business.industry cirrhosis Sequence Analysis DNA biochemical phenomena metabolism and nutrition genotype 1b medicine.disease Settore MED/17 digestive system diseases Mutation Cancer research business Carcinogenesis Biomarkers |
| Zdroj: | Viruses Volume 13 Issue 5 Viruses, Vol 13, Iss 743, p 743 (2021) |
| ISSN: | 1999-4915 |
| DOI: | 10.3390/v13050743 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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