Abstract 3752: GSTT1 and GSTM1 null genotypes may increase risk of HCV-associated HCC

Abstract

Abstract Introduction: Oxidative stress plays an important role in hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC). Glutathione S-transferases (GSTs) prevent oxidative stress associated cellular damage, catalyzing the conjugation of electrophilic compounds with glutathione. Partial or complete deletions of GST theta 1 (GSTT1) and mu 1 (GSTM1) have been associated with chronicity of HCV infection. However, data on the role of these null genotypes in progression to HCC is lacking. We investigated whether GSTT1 and GSTM1 modify the association between HCV and HCC in a case-control study in Egypt. Methods: Participants were recruited at the National Cancer Institute of Cairo University. Cases of HCC were confirmed on pathology, alpha-fetoprotein levels and imaging. Non-cancer controls, representative of the general population with respect to HCV prevalence, were frequency matched to cases on age, sex, and area of residence. HCV antibodies were measured in blood samples by enzyme-linked immunosorbent assay, and HCV RNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). Homozygous deletions in GSTT1 and GSTM1 were determined by separate multiplex PCR methods. For these analyses, participants with active HBV were excluded. Logistic regression was used to analyze the risk of HCC associated with HCV after stratifying by GSTT1 and GSTM1 genotype. Additive interaction of HCV and null GST genotypes in HCC risk were determined by calculating the interaction contrast ratio (ICR). All analyses were adjusted for age, sex, current smoking, alcohol intake, urban/rural status, and pesticide use. Results: Compared to controls, HCC cases were more likely to be older, married, non-smokers, living in rural areas, and exposed to agricultural pesticides. HCV infection was a strong risk factor for HCC in this population [adjusted odds ratio (aOR): 13.6, 95% confidence interval (CI): 9.7-18.9]. GSTT1 and GSTM1 polymorphisms alone were not associated with HCC risk. However, the association of HCV with HCC was markedly stronger in patients with null GSTT1 genotype [aOR (95% CI): 23.9 (12.8-44.9) for null vs. 11.4 (7.6-17.1) for non-null]. The observations were similar for GSTM1 genotype [aOR (95% CI): 17.7 (11.1-28.5) for null vs. 10.0 (6.2-16.1) for non-null]. Additive positive interaction, as determined by an ICR value greater than zero, between HCV and null GSTT1 was significant for HCC risk [ICR (95% CI): 10.9 (2.6-41.9)]. However, the ICR for GSTM1 and HCV interaction was not statistically significant [ICR (95% CI): 2.9 (−1.7-11.1)]. Conclusions: Chronic HCV carriers with null GST genotypes are more likely to have HCC as compared to those with non-null genotypes. Studies are needed to confirm these findings and investigate the exact mechanisms underlying HCC susceptibility associated with the null GST genotypes in chronic HCV patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3752. doi:10.1158/1538-7445.AM2011-3752