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Variants in the -Methylacyl-CoA Racemase Gene and the Association with Advanced Distal Colorectal Adenoma

¹ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, and ² Core Genotyping Facility, Division of Cancer Epidemiology and Genetics, Advanced Technology Program, SAIC Frederick Inc., NCI-Frederick Frederick, Maryland; Departments of ³ Epidemiology and ⁴ Biostatistics, Johns Hopkins Bloomberg School of Public Health; ⁵ The James Buchanan Brady Urological Institute and the Department of Urology, Johns Hopkins School of Medicine; and ⁶ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Sarah E. Daugherty, Divison of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS Rm 8113, Bethesda, MD 20892. Phone: 301-451-8789; Fax: 301-402-1819. E-mail: daughers{at}mail.nih.gov

Background: -Methylacyl-CoA racemase (AMACR), an enzyme involved in oxidation of branched chain fatty acids and cholesterol metabolites, as well as ibuprofen metabolism, is overexpressed in colorectal adenomas and cancer. AMACR gene variants have been associated with hereditary prostate cancer, but no studies have evaluated their etiologic role in colorectal carcinogenesis.

Methods: We conducted a case-control study of 725 advanced distal colorectal adenoma cases and 729 frequency-matched controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Seven AMACR polymorphisms were genotyped. Unconditional logistic regression models were used to evaluate the associations adjusting for age at randomization and gender.

Results: The 201L allele of S201L [TT versus CC: odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.15-2.62; TC versus CC: OR, 1.17; 95% CI, 0.93-1.49] and the 277E allele of K277E (GG versus AA: OR, 1.66; 95% CI, 1.03-2.68; GA versus AA: OR, 1.21; 95% CI, 0.96-1.53) were associated with increased risk of advanced distal colorectal adenoma (both P_trend 0.02); the TGTGCG haplotype of six informative single nucleotide polymorphisms was also associated with increased risk (OR, 1.27; 95% CI, 1.03-1.55). Regular ibuprofen users who were homozygous for the variant allele at either M9V or D175G were at reduced risk for adenoma (both P_interaction < 0.05).

Conclusion: Our study identified variants in AMACR associated with advanced distal colorectal adenoma and pointed to potential interactions with ibuprofen use. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1536–42)