This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pande, M. Articles by Frazier, M. L. Search for Related Content PubMed PubMed Citation Articles by Pande, M. Articles by Frazier, M. L.

Genetic Variation in Genes for the Xenobiotic-Metabolizing Enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and Susceptibility to Colorectal Cancer in Lynch Syndrome

Departments of ¹ Epidemiology, ² Gastrointestinal Medicine and Nutrition, and ³ Pathology, The University of Texas M. D. Anderson Cancer Center; ⁴ Program in Human and Molecular Genetics, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Marsha L. Frazier, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1365, 1155 Hermann P. Pressler Boulevard, Houston, TX 77030. Phone: 713-792-3393; Fax: 713-745-1163; E-mail: mlfrazier{at}mail.mdanderson.org.

Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages, 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA, 1.78; 95% confidence interval, 1.16-2.74; P = 0.008; hazard ratio for TC relative to TT, 1.53; 95% confidence interval, 1.06-2.22; P = 0.02]. Because homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome because they modify the age of colorectal cancer onset by up to 4 years. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2393–401)