Genomewide Association Study of Prostate Cancer

描述（由申请人提供）：前列腺癌的发病率和死亡率在不同种族群体之间差异很大，有明确的证据表明遗传因素影响男性患前列腺癌的风险。然而，事实证明，找到导致这种常见但复杂疾病的遗传变异是困难的。传统的全基因组连锁和候选基因研究产生了模棱两可的结果。这部分是由于连锁研究检测具有适度影响的常见变异的能力降低以及候选基因研究中评估的基因数量有限。一种更有希望的方法是使用单核苷酸多态性（SNP）和拷贝数变异（CNV）的全基因组关联研究来寻找导致前列腺癌的遗传变异。最近对高加索人前列腺癌的GWA研究发现了一些非常有希望的相关性。我们建议在这些令人兴奋的结果的基础上，进行一项关于SNP和CNV如何影响少数群体前列腺癌风险的全基因组关联研究。具体来说，我们将研究2,000例前列腺癌病例和2,000例年龄和种族匹配的对照（2,000名非洲裔美国人和2,000名亚裔美国人），这些病例和对照都在北方加州Kaiser Permanente人群中。我们的第一个目标是获得这种嵌套病例对照人群的生物标本。第二，我们将在整个研究人群中对新的Affyssin SNP Array 6.0进行基因分型。鉴于基因分型成本的迅速降低，这种单阶段设计是非常有效的，并且对于全面评估SNP和CNV是必要的。我们的第三个目标是研究Array测量的SNP与前列腺癌之间的关联。第四，我们将从阵列中确定CNV，并评估它们如何影响前列腺癌风险（即，单独和与SNP结合）。4,000名受试者的研究样本量和全面的SNP Array 6.0信息为检测SNP和CNV与前列腺癌的相关性提供了足够的把握度。通过将这项全基因组关联研究集中在前列腺癌风险最高和最低的两个种族群体上，并研究来自具有高度代表性的Kaiser Permanente人群的受试者，该项目提供了一个绝佳的机会来确定这种疾病在未充分研究的人群中的遗传原因。发现这些遗传因素对于改善筛查、治疗方式和了解前列腺癌的生物学基础具有重要意义。公共卫生相关性：前列腺癌是最常见和明显的家族性/遗传性癌症之一，但发现这种疾病的原因已被证明是极其困难的。我们努力破译少数人群中前列腺癌的遗传基础，将有助于改善筛查，治疗和我们对这种疾病的整体理解。这些进展将改善男性的整体健康状况，为研究不足的人群提供有关前列腺癌个体和人群水平风险的急需信息。

DESCRIPTION (provided by applicant): The morbidity and mortality due to prostate cancer varies substantially across ethnic groups, and there is clear evidence that genetic factors impact a man's risk of prostate cancer. However, finding genetic variants that cause this common but complex disease has proven difficult. Traditional genome-wide linkage and candidate gene studies have produced equivocal results. This is due in part to the reduced power of linkage studies to detect common variants with modest effects and the limited number of genes evaluated in candidate gene studies. A more promising approach is to search for prostate cancer causing genetic variants using a genome- wide association study of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Recent GWAs of prostate cancer focused on Caucasians have detected a number of extremely promising associations. We propose building on these exciting results with large a genome-wide association study of how SNPs and CNVs impact prostate cancer risk in minority populations. Specifically, we will study 2,000 prostate cancer cases and 2,000 age and ethnicity matched controls (2,000 African-Americans, and 2,000 Asian-Americans) nested in the Northern California Kaiser Permanente population. Our first aim is to obtain biospecimens on this nested case-control population. Second, we will genotype the new Affymetrix SNP Array 6.0 on the entire study population. This single-stage design is highly efficient in light of the rapidly decreasing genotyping costs, and is necessary to fully evaluate both SNPs and CNVs. Our third aim will investigate the association between the SNPs measured by the Array and prostate cancer. Fourth, we will determine CNVs from the Array, and evaluate how they effect prostate cancer risk (i.e., alone and in conjunction with the SNPs). The study sample size of 4,000 subjects and the comprehensive SNP Array 6.0 information provide sufficient power for detecting SNP and CNV associations with prostate cancer. By focusing this genome-wide association study on the two ethnic groups with the highest and lowest risks of prostate cancer and studying subjects from the highly representative Kaiser Permanente population this project provides an outstanding opportunity to determine the genetic causes of this disease in understudied populations. Finding such genetic factors will have substantial significance with regard to improving screening, treatment modalities, and understanding the biologic basis of prostate cancer. PUBLIC HEALTH RELEVANCE: Prostate cancer is one of the most common and clearly familial / genetic cancers, but finding the cause of this disease has proven extremely difficult. Our efforts toward deciphering the genetic basis of prostate cancer in minority populations will help improve screening, treatment, and our overall understanding of this disease. These advances will improve the overall health of men, providing much needed information about individual- and population-level risks of prostate cancer within understudied populations.