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中差异很大，并且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基因变异很困难。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。一种更有前景的方法是利用单核苷酸多态性（SNP）和拷贝数变异（CNV）的全基因组关联研究来寻找引起前列腺癌的遗传变异。最近针对白种人的前列腺癌 GWA 发现了许多极有前景的关联。我们建议在这些令人兴奋的结果的基础上，开展一项大型全基因组关联研究，研究 SNP 和 CNV 如何影响少数群体的前列腺癌风险。具体来说，我们将研究居住在北加州 Kaiser Permanente 人群中的 2,000 名前列腺癌病例和 2,000 名年龄和种族匹配的对照（2,000 名非裔美国人和 2,000 名亚裔美国人）。我们的首要目标是获得该嵌套病例对照群体的生物样本。其次，我们将对整个研究群体使用新的 Affymetrix SNP Array 6.0 进行基因分型。鉴于基因分型成本迅速下降，这种单阶段设计非常高效，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阵列测量的 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 与前列腺癌的关联提供了足够的能力。通过将这项全基因组关联研究的重点放在前列腺癌风险最高和最低的两个种族群体上，并研究来自高度代表性的凯撒永久人群的受试者，该项目提供了一个绝佳的机会来确定受研究人群中这种疾病的遗传原因。寻找此类遗传因素对于改善前列腺癌的筛查、治疗方式和了解其生物学基础具有重要意义。公共卫生相关性：前列腺癌是最常见且明显的家族/遗传性癌症之一，但事实证明，找到这种疾病的病因极其困难。我们为破译少数群体前列腺癌的遗传基础所做的努力将有助于改善筛查、治疗和我们对这种疾病的整体了解。这些进步将改善男性的整体健康状况，提供有关未充分研究人群中个人和人群前列腺癌风险的急需信息。

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.