CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer

Laura Silvestri, Laura Sonzogni, Annalisa De Silvestri, Chiara Gritti, Luciana Foti, Claudio Zavaglia, Michela Leveri, Agostino Cividini, Mario U. Mondelli, Emilio Civardi, Enrico M. Silini

Research output: Contribution to journalArticle

Abstract

Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus-infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the X2 test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects.

Original languageEnglish
Pages (from-to)310-317
Number of pages8
JournalInternational Journal of Cancer
Volume104
Issue number3
DOIs
Publication statusPublished - Apr 10 2003

Keywords

  • Chronic liver disease
  • DNA polymorphism
  • Drug-metabolizing enzymes
  • Genetic susceptibility

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Silvestri, L., Sonzogni, L., De Silvestri, A., Gritti, C., Foti, L., Zavaglia, C., Leveri, M., Cividini, A., Mondelli, M. U., Civardi, E., & Silini, E. M. (2003). CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer. International Journal of Cancer, 104(3), 310-317. https://doi.org/10.1002/ijc.10937