Alpha-methylacyl-CoA racemase: A candidate gene for prostate cancer and advanced distal colorectal adenomas in the prostate, lung, colorectal, and ovarian cancer screening trial

Introduction. Alpha-methylacyl-CoA racemase (AMACR), which plays a critical role in the oxidation of pristanic acid and cholesterol metabolites, has been found to be overexpressed in prostate and colorectal cancer, as well as their precursor lesions. While little is known about the etiological role of AMACR, differences in allele frequencies among hereditary prostate cancer cases and controls have been reported. To better understand the etiological scope and importance of AMACR genetic variants in the general population, we evaluated the association between AMACR polymorphisms and prostate cancer and colorectal adenomas in a population-based sample. In addition, we explored the modifying role of two AMACR substrates, ibuprofen and branched chain fatty acids.; Methods. Two case-control studies were nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial with 1317 prostate cancer cases, 772 advanced distal colorectal adenoma cases, and their frequency-matched controls. Seven AMACR polymorphisms (EX5+90G>A, IVS4+3803C>G, EX4-23G>T, EX4+50C>T, EX3-29A>G, IVS1+169G>T, EX1+114A>G) were genotyped using either the TaqMan or MGBeclipse platform. All participants filled out a risk factor questionnaire and a food frequency questionnaire at baseline.; Results. Four AMACR polymorphisms (EX1+114A>G, EX3-29A>G, EX4+50C>T and EX5+90G>A) were associated with nonsignificant reductions in risk of prostate cancer and increased risk for advanced distal colorectal adenomas. The GCGTGT haplotype was associated with an increased risk of advanced stage prostate cancer and advanced distal colorectal adenomas. Statistically significant reductions in risk for prostate cancer were observed among men with the four variant alleles who reported regular ibuprofen use. Evidence for a statistically significant interaction between two polymorphisms and ibuprofen use was found to reduce risk for colorectal adenomas as well. No significant interactions were identified between the AMACR polymorphisms and primary food sources of branched chain fatty acids in either the prostate or colorectal sample.; Conclusion. Despite the different points in the natural history of cancer progression and the dissimilar sites, our results suggest that the AMACR gene harbors a variant or variants that alter risk for cancer at both sites. Regular ibuprofen use may modify the association between particular AMACR genetic variants and prostate cancer and advanced distal colorectal adenomas.