Polymorphic variants in alpha-methylacyl-CoA racemase and prostate cancer.
BACKGROUND
Alpha-methylacyl-CoA racemase (AMACR), which prepares branched chain fatty acids to be metabolized for energy and is implicated in the activation of the COX-inhibiting form of ibuprofen, is overexpressed in prostate cancer and its precursor lesions. Significant differences in AMACR allele frequencies have been reported for hereditary prostate cancer (HPC), but the relevance of AMACR in the context of its substrates have not been studied.


METHODS
We conducted a nested case-control study of 1,318 prostate cancer cases and 1,842 controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Five non-synonymous (nsSNP) and two intronic AMACR polymorphisms were genotyped. Conditional logistic regression models were used to evaluate the associations between the genetic variants and prostate cancer.


RESULTS
Overall, prostate cancer was not related to AMACR gene variants; however, risks for prostate cancer were significantly reduced among regular ibuprofen users who carried allele variants at four nsSNP loci (M9V, D175G, S201L, and K277E; all P(trend) < 0.05) or carried the TGTGCG haplotype (OR = 0.65; 95% CI 0.44-0.97). No AMACR-related associations were noted among nonregular ibuprofen users (all P(interaction) > 0.33).


CONCLUSIONS
AMACR gene variants were unrelated to prostate cancer overall in this study. The protective associations observed among ibuprofen users suggest that AMACR gene variants may enhance the chemopreventive effects of ibuprofen on prostate cancer risk.
Daugherty
Sarah E
SE
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. daughers@mail.nih.gov
Shugart
Yin Yao
YY
Platz
Elizabeth A
EA
Fallin
M Daniele
MD
Isaacs
William B
WB
Pfeiffer
Ruth M
RM
Welch
Robert
R
Huang
Wen-Yi
WY
Reding
Douglas
D
Hayes
Richard B
RB
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D016022:Case-Control Studies; D018890:Chemoprevention; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D019998:Racemases and Epimerases / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005819:Genetic Markers; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase; D007052:Ibuprofen