Polymorphic variation of CYP1A1 is associated with the risk of gastric cardia cancer: a prospective case?cohort study of cytochrome P-450 1A1 and GST enzymes

Abstract

To determine if genetic polymorphisms of CYP1A1, GSTM1, GSTP1, or GSTT1 are associated with an increased risk of developing esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), or either in a high-risk Asian population. We conducted a case-cohort analysis with 5 years of prospective follow-up. The analytical cohort contained 642 individuals who participated in either the Dysplasia Trial (DT) or the General Population (GPT) of the Nutrition Intervention Trials conducted in Linxian, China, and included 131 cases of ESCC and 90 cases of GCC. Genotyping analysis was performed on DNA extracted from red blood cells using a PureGene kit (Gentra Systems, Inc., Minneapolis, MN) and real-time PCR analysis amplification (Taq-Man). Relative risks and 95% confidence intervals were estimated using the case - cohort estimator for the Cox proportional hazards models. p-values from nested models with genotyping variables came from score tests. The relative risks for developing ESCC, GCC, or either cancer were calculated in the entire analytic cohort for GSTM1, P1*B (A313G), and T1 and CYP1A1*2A (T3801C) and *2C (A2455G) genotypes, and no significant associations were identified. However, because of the difference in cancer risks between the DT (9.3 cases per 1000 person years) and the GPT (5.3 cases), the analytical cohort was stratified by trial; the DT participants who were heterozygous or homozygous for the variant-allele at CYP1A1*2A had a reduced risk for developing GCC (adjusted RR (95% CI) 0.47 (0.23-1.00) p = 0.037). This study found an association for the CYP1A1*2A variant allele and a reduced risk of GCC in people at high risk for development of this disease. This finding is consistent with previous studies suggesting that substrates for the cytochrome P-450 1A1 metabolic pathway, such as polycyclic aromatic hydrocarbons, may be etiologically significant in this high-risk region.