Genetic Epidemiology of Prostate Cancer Risk and Progression

描述(申请人提供)：前列腺癌是一种常见但复杂的疾病，围绕其自然病史有许多悬而未决的问题。这些问题包括对筛查、检测和治疗的担忧，反映了前列腺癌的本质异质性：一些肿瘤仍处于潜伏状态，对发病率几乎没有影响，而另一些肿瘤进展迅速，具有潜在的致命性。遗传因素可能是其中一些差异的基础，我们建议在一个大的、特征良好的研究人群中对前列腺癌风险和进展的遗传基础进行全面评估。特别是，我们将研究跨越外显子组的RAR功能变异和跨越基因组的常见SNPs。我们的样本包括8,078例前列腺癌病例和8,078名年龄和种族匹配的对照，这些对照嵌套在Kaiser/USCF基因、环境和健康队列研究项目中。该人群拥有现有的全基因组SNP测量方法，并统一收集关于前列腺癌筛查、诊断和进展的临床信息。我们计划在病例和对照上输入新的外显子组阵列，以评估整个人类基因组蛋白质编码区的功能变异。有了这些数据，我们将解决我们的假设，即这些遗传因素可以用来预测前列腺癌风险和进展的变异，并奠定越来越大的比例。该项目提供了一个有效和创新的机会，以全面了解这些因素如何影响前列腺癌的自然历史。我们的发现应该为疾病的潜在机制提供重要的见解，最终目标是帮助改进前列腺癌的筛查和治疗。

DESCRIPTION (provided by applicant): Prostate cancer is a common but complex disease with a number of unresolved issues surrounding its natural history. These include concerns with screening, detection, and treatment, and reflect the substantial heterogeneity in prostate tumors: some will remain latent and have little impact on morbidity, whereas others progress rapidly in a potentially lethal manner. Genetic factors likely underlie some of these differences, and we propose a comprehensive evaluation of the genetic basis of prostate cancer risk and progression in a large, well-characterized study population. In particular, we will investigate rar functional variants across the exome and common SNPs across the genome. Our sample encompasses 8,078 prostate cancer cases and 8,078 age and ethnicity matched controls nested within the Kaiser / USCF Research Program on Genes, Environment and Health cohort. This population has existing genome-wide SNP measures, and uniformly collected clinical information on prostate cancer screening, diagnoses, and progression. We plan to type the new exome array on the cases and controls to assess the functional variants in protein coding regions across the human genome. With these data we will address our hypothesis that these genetic factors can be used to predict-and underlie an increasing proportion of the variation in-prostate cancer risk and progression. This project provides an efficient and innovative opportunity to obtain a comprehensive understanding of how these factors impact the natural history of prostate cancer. Our findings should supply important insights into the underlying mechanism of disease, with the ultimate goal of helping to improve screening and treatment for prostate cancer.