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，随着婴儿潮一代的老龄化，预计其对社会的巨大发病率和死亡负担将会增加。雌激素对前列腺癌的致癌作用已经在动物、细胞系和组织表达研究中得到了清楚的证明。矛盾的是，目前人们对使用合成雌激素治疗晚期前列腺癌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。这项研究将调查雌激素受体亚型ESR1(ESR1)和ESR2(ESR2)、将睾酮转化为雌激素的芳香酶基因(CYP19A1)以及编码雌激素分解代谢酶(CYP1A1和CYP1B1)的基因的前列腺癌风险和胚系遗传变异。我们提出了以下主要目标：1)在一项基于人群的病例对照研究中，利用标记单核苷酸多态(SNPs)对ESR1、ESR2、CyP19A1、CyP1A1和CyP1B1进行综合分型，并估计与单个SNPs、单倍型和多基因途径相关的相对风险。2)根据疾病侵袭性指标评估基因与前列腺癌风险的关系。我们还提出了以下次要目标：(1)检验肥胖作为一种可能的效应修饰物与总体前列腺癌风险相关的基因型；(2)通过计算前列腺癌复发/进展和死亡率的风险，确定基因型是否与不良患者预后相关；(3)测量从前列腺癌根治术患者中采集的实体瘤组织样本中ESR1和ESR2基因的表达，并将这些结果与ESR1和ESR2基因型相关联；以及(4)在接受雄激素剥夺治疗的男性中，调查基因型与患者预后的相关性。为了实现这些目标，我们将在现有人群研究的基础上，对1,457例经组织学证实的PCa病例和1,351例没有PCa病史的年龄频率匹配的对照组进行研究。将使用公开的数据来选择SNPs，以全面涵盖每个基因中常见的单倍型变异。前列腺癌风险将使用调整后的非条件Logistic回归和多分类回归进行估计。疾病复发/进展的风险和前列腺癌的死亡率将使用COX比例风险(PH)回归进行估计。这项研究的结果可能为雌激素途径基因如何改变前列腺癌的风险提供新的信息，更重要的是，谁可能面临更具侵袭性的疾病的风险。此外，这项研究可能会确定与基因类型相互作用的患者特征，从而增加风险。最后，研究结果可作为进一步探索新的雌激素或抗雌激素治疗方法的先导数据。

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.