Estrogen Pathway Genes and Association with Prostate Cancer Risk

描述（由申请人提供）： 前列腺癌（PCa）是一个主要的公共卫生问题，其对社会的重大发病率和死亡率的负担预计将随着婴儿潮一代的老龄化而增长。雌激素对前列腺的致癌作用已在动物、细胞系和组织表达研究中得到明确证实。巧合的是，目前对使用合成雌激素治疗晚期PCa患者的兴趣重新抬头。雌激素的双重作用似乎是受体介导的，并依赖于类固醇途径的相互作用。本研究将调查前列腺癌风险和编码雌激素受体亚型ESR 1（ESR 1）和ESR 2（ESR 2）的基因、编码将睾酮转化为雌激素的芳香酶（CYP 19 A1）的基因以及编码雌激素催化酶（CYP 1A 1和CYP 1B 1）的基因的种系遗传变异。我们提出以下主要目的：1）在基于人群的PCa病例对照研究中，使用标签单核苷酸多态性（SNP）对ESR 1、ESR 2、CYP 19 A1、CYP 1A 1和CYP 1B 1进行综合基因型分析，并估计与单个SNP、单倍型和多基因途径相关的相对风险。2)评估基因型与前列腺癌的风险，根据疾病的侵袭性措施。我们还提出了以下次要目标：（1）研究肥胖作为基因型与PCa总体风险相关性的可能影响因素;（2）通过计算PCa复发/进展风险和死亡率，确定基因型是否与不良患者结局相关;（三）为了测量从接受根治性乳腺癌切除术的病例中采集的实体瘤组织样本中的ESR 1和ESR 2基因表达，并将这些发现与ESR 1和ESR 2基因型;（4）研究雄激素剥夺治疗男性患者基因型与患者结局的关系。为了实现这些目标，我们将在现有的基于人群的研究基础上，对1，457例组织学确诊的PCa病例和1，351例年龄频率匹配的无PCa病史的对照进行研究。将使用公开可用的数据选择SNP，以全面覆盖每个基因内的常见单倍型变异。将使用校正的非条件logistic和多分类回归估计前列腺癌风险。将使用考克斯比例风险（PH）回归估计疾病复发/进展风险和前列腺特异性癌症死亡率。这项研究的结果可能会提供新的信息，雌激素途径基因如何改变前列腺癌的风险，更重要的是，谁可能处于更积极的疾病形式的风险。此外，这项研究可能会确定与基因型相互作用以增加风险的患者特征。最后，结果可以作为试点数据，以进一步探索新的雌激素或抗雌激素治疗方法。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a major public health concern for which the substantial morbidity and mortality burden on society is expected to grow with the aging baby boom generation. The carcinogenic effects of estrogen on the prostate have been clearly demonstrated in animal, cell line, and tissue expression studies. Paradoxically, there is a current resurgence of interest in using synthetic estrogens to treat patients with advanced PCa. The dual effect of estrogen appears to be receptor mediated and dependant on steroid pathway interactions. This study will investigate PCa risk and germline genetic variation in genes encoding the estrogen receptors subtypes ESR1 (ESR1) and ESR2 (ESR2), the gene encoding aromatase (CYP19A1) that converts testosterone to estrogen, and the genes that encode estrogen catabolism enzymes (CYP1A1 and CYP1B1). We propose the following primary aims: 1) To comprehensively genotype ESR1, ESR2, CYP19A1, CYP1A1 and CYP1B1 using tag single nucleotide polymorphisms (SNPs) in a population-based case-control study of PCa and estimate relative risks associated with individual SNPs, haplotypes, and within multigenic pathways. 2) To evaluate genotypes association with PCa risk according to measures of disease aggressiveness. We also propose the following secondary aims: (1) To examine obesity as a possible effect modifier in genotype associations with overall PCa risk; (2) To determine whether genotypes are associated with adverse patient outcomes by calculating risk of PCa recurrence/progression and mortality; (3) To measure ESR1 and ESR2 gene expression in solid tumor tissue samples taken from cases undergoing radical prostatectomy and correlate these findings with ESR1 and ESR2 genotypes; and, (4) To investigate associations of genotypes with patient outcomes among men treated with androgen deprivation therapy. To accomplish these aims, we will to build upon an existing population-based study of 1,457 histologically confirmed PCa cases and 1,351 age-frequency matched controls without a history of PCa. The SNPs will be selected using publicly available data to comprehensively cover common haplotype variation within each gene. Prostate cancer risk will be estimated using adjusted unconditional logistic and polytomous regression. Risk of disease recurrence/progression and prostate-specific cancer mortality will be estimated using Cox proportional hazards (PH) regression. Results from this study may provide novel information on how estrogen pathway genes alter risk of PCa and, more importantly, who may be at risk for more aggressive forms of the disease. In addition, this study may identify patient characteristics that interplay with genotypes to increase risk. Lastly, results may serve as pilot data to further explore novel estrogen or anti-estrogen therapeutic approaches.