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之间有很大差异，有明确的证据表明遗传因素会影响男性患前列腺癌的风险。然而，发现导致这种常见但复杂疾病的基因变异已被证明是困难的。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。这在一定程度上是由于连锁研究检测普通变异的能力较低，而且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（CNVs）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GWAs发现了一些极有希望的关联。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CNVs如何影响少数人群前列腺癌风险的大型全基因组关联研究。具体来说，我们将研究2000例前列腺癌病例和2000例年龄和种族匹配的对照（2000名非洲裔美国人和2000名亚裔美国人），这些对照嵌套在北加州凯撒永久医疗机构的人口中。我们的第一个目标是获得这种巢状病例对照种群的生物标本。其次，我们将在整个研究群体上对新的Affymetrix SNP Array 6.0进行基因分型。考虑到快速降低的基因分型成本，这种单阶段设计是高效的，并且是充分评估snp和CNVs的必要条件。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系。第四，我们将从阵列中确定CNVs，并评估它们如何影响前列腺癌风险（即单独或与snp结合）。4000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力量。通过将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，并从极具代表性的Kaiser Permanente人群中研究受试者，该项目为在研究不足的人群中确定这种疾病的遗传原因提供了一个绝佳的机会。发现这些遗传因素对于改善前列腺癌的筛查、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全面了解。这些进展将改善男性的整体健康状况，在未充分研究的人群中提供关于个人和群体水平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.