Daugherty Sarah E, Shugart Yin Yao, Platz Elizabeth A, Fallin M Daniele, Isaacs William B, Pfeiffer Ruth M, Welch Robert, Huang Wen-Yi, Reding Douglas, Hayes Richard B
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Prostate. 2007 Oct 1;67(14):1487-97. doi: 10.1002/pros.20635.
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.
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.
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).
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.
α-甲基酰基辅酶A消旋酶（AMACR）可使支链脂肪酸代谢以产生能量，且与布洛芬的环氧化酶抑制形式的激活有关，在前列腺癌及其前驱病变中过度表达。已有报道称遗传性前列腺癌（HPC）的AMACR等位基因频率存在显著差异，但尚未研究AMACR在其底物背景下的相关性。
我们对来自前列腺、肺、结肠和卵巢（PLCO）癌症筛查试验筛查组的1318例前列腺癌病例和1842例对照进行了巢式病例对照研究。对5个非同义（nsSNP）和2个内含子AMACR多态性进行基因分型。使用条件逻辑回归模型评估基因变异与前列腺癌之间的关联。
总体而言，前列腺癌与AMACR基因变异无关；然而，在四个nsSNP位点（M9V、D175G、S201L和K277E；所有P（趋势）<0.05）携带等位基因变异或携带TGTGCG单倍型的规律使用布洛芬的使用者中，前列腺癌风险显著降低（OR = 0.65；95% CI 0.44 - 0.97）。在不规律使用布洛芬的使用者中未发现与AMACR相关的关联（所有P（交互作用）> 0.33）。
在本研究中，AMACR基因变异总体上与前列腺癌无关。在布洛芬使用者中观察到的保护关联表明，AMACR基因变异可能增强布洛芬对前列腺癌风险的化学预防作用。
