Estrogen Pathway Genes and Association with Prostate Cancer Risk

雌激素途径基因及其与前列腺癌风险的关联

基本信息

批准号：
7590785
负责人：
JANET L STANFORD
金额：
$ 8.8万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-18 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7590785
关键词：
Address Advocate African American Age Aging Androgens Animals Aromatase Baby Booms Blood Body mass index CYP19A1 gene CYP1A1 gene CYP1B1 gene Case-Control Studies Catabolism Caucasians Caucasoid Race Cell Line Characteristics Complex Data Diagnostic Neoplasm Staging Disease Disease Progression Disease regression ESR1 gene ESR2 gene Enzymes Estrogen Antagonists Estrogen Receptors Estrogens Etiology Frequencies Gene Expression Generations Genes Genetic Genetic Polymorphism Genetic Variation Genotype Gleason Grade for Prostate Cancer Gonadal Steroid Hormones Haplotypes Histologic Hypermethylation Incidence Individual Interview Lead Light Link Logistics Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Molecular Morbidity - disease rate Obesity Outcome Participant Pathway interactions Patients Pattern Persons Play Population Prostate Public Health Radical Prostatectomy Receptor Gene Recording of previous events Recurrence Relative (related person)Relative Risks Research Risk Role Selective Estrogen Receptor Modulators Serum Single Nucleotide Polymorphism Societies Solid Neoplasm Steroids Techniques Testosterone Therapeutic Tissue Sample Tissues Tumor Tissue Tumor stage Variant base cancer recurrence cancer risk carcinogenesis deprivation disorder risk hazard interest men mortality novel receptor tumor progression xenoestrogen

项目摘要

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.

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，预计随着婴儿潮一代的老龄化，其给社会带来的巨大发病率和死亡率负担将会增加。动物、细胞系和组织表达研究清楚地证明了雌激素对前列腺的致癌作用。矛盾的是，目前人们对使用合成雌激素治疗晚期 PCa 患者的兴趣重新兴起。雌激素的双重作用似乎是受体介导的，并且依赖于类固醇途径的相互作用。本研究将调查编码雌激素受体亚型 ESR1 (ESR1) 和 ESR2 (ESR2) 的基因、编码将睾酮转化为雌激素的芳香酶 (CYP19A1) 的基因以及编码雌激素分解代谢酶的基因 (CYP1A1) 的 PCa 风险和种系遗传变异。和 CYP1B1)。我们提出以下主要目标：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 ESR1、ESR2、CYP19A1、CYP1A1 和 CYP1B1 进行全面基因分型，并估计与个体 SNP、单倍型相关的相对风险，并且在多基因途径内。 2) 根据疾病侵袭性的测量来评估基因型与 PCa 风险的关联。我们还提出以下次要目标：（1）研究肥胖作为基因型与总体 PCa 风险关联的可能效应调节剂； (2) 通过计算 PCa 复发/进展和死亡率的风险来确定基因型是否与不良患者结局相关； (3) 测量接受根治性前列腺切除术的实体瘤组织样本中的ESR1和ESR2基因表达，并将这些结果与ESR1和ESR2基因型相关联； (4) 研究接受雄激素剥夺疗法的男性中基因型与患者结果的关联。为了实现这些目标，我们将在现有的基于人群的研究的基础上，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。 SNP 将使用公开数据进行选择，以全面涵盖每个基因内常见的单倍型变异。将使用调整后的无条件逻辑回归和多元回归来估计前列腺癌风险。将使用 Cox 比例风险 (PH) 回归来估计疾病复发/进展的风险和前列腺特异性癌症死亡率。这项研究的结果可能提供关于雌激素途径基因如何改变 PCa 风险的新信息，更重要的是，哪些人可能面临罹患更具侵袭性疾病的风险。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，结果可以作为进一步探索新的雌激素或抗雌激素治疗方法的试点数据。