Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer
Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer
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DOI：
10.1158/1055-9965.epi-06-0767
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Thibodeau, Stephen N.
中科院分区：
文献类型：
--
作者：
Cunningham, Julie M.;Hebbring, Scott J.;Thibodeau, Stephen N.
先前的研究表明，参与雄激素代谢途径的酶是前列腺癌的易感因素。作为基因毒素发挥作用的雌激素代谢物也被认为是危险因素。在这项研究中，我们系统地检验了以下假设：参与雄激素和雌激素代谢途径的酶的常见遗传变异会增加散发性和家族性前列腺癌的风险。通过这两条途径，对 25 个基因中的 46 个多态性（34 个单核苷酸多态性、10 个短串联重复多态性和 2 个无效等位基因）进行了可能的关联测试。测试的基因包括来自雄激素途径的 PRL、LHB、CYP11A1、HSD3B1、HSD3B2、HSD17B2、CYP17、SRD5A2、AKR1C3、UGT2B15、AR、SHBG 和 KLK3 以及 CYP19、HSD17B1、CYP1A1、CYP1A2、CYP1B1、COMT、来自雌激素途径的 GSTP1、GSTT1、GSTM1、NQO1、ESR1 和 ESR2。病例对照研究设计用于两组病例：具有强烈前列腺癌家族史的家族病例（n = 438，来自 178 个家庭）和具有阴性前列腺癌家族史的散发病例（n = 499）。对照 (n = 493) 来自基于人群的收集。我们的结果提供了与家族性或散发性前列腺癌与四个基因多态性相关的提示性发现：AKR1C3、HSD17B1、NQO1 和 GSTT1。在八个基因的单核苷酸多态性中观察到与临床变量（疾病阶段、分级和/或淋巴结状态）相关的其他提示性发现：HSD3B2、SRD5A2、SHBG、ESR1、CYP1A1、CYP1B1、GSTT1 和 NQO1。然而，在对多重比较进行适当校正后，所有发现均不具有统计学意义。鉴于每个多态性的比值比的点估计值均 < 2.0，因此需要更大的样本量进行确认。
Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are < 2.0, much larger sample sizes will be required for confirmation.