Genome-wide scan for genetic variants associated with early-onset prostate cancer

描述(申请人提供)：2008年，前列腺癌(PCA)是美国最常见的男性癌症，估计新增病例186,320例，是与癌症相关的死亡的第二大原因，估计有28,660例与癌症相关的死亡。识别增加前列腺癌易感性的基因或其他基因组变异将通过提供与前列腺癌发展有关的有价值的生物学数据来影响公众健康。前列腺癌基因的发现还可能导致前列腺癌的新治疗，并为识别患有前列腺癌风险增加的男性提供了一种有价值的额外筛查工具。早期诊断为前列腺癌的男性比晚年确诊的男性更有可能死于这种疾病，而且已有研究表明，早发性(EO)前列腺癌更有可能是由于遗传风险因素造成的，而不是较晚发病的疾病。在这项建议中，我们描述了一种有效和强大的多阶段全基因组关联扫描(GWAS)，以寻找与EO PCA相关的遗传变异。在第一阶段，我们建议对来自密歇根大学(UM)的1000例高加索人EO PCA病例进行约550,000个SNP的基因分型。将评估这些UM EO PCA病例和来自Illumina iControlDB的3,000个免费对照之间观察到的等位基因频率的差异，以确定第二阶段跟进的SNPs子集。我们将对来自约翰霍普金斯大学(JHU)的1,250例高加索人EO PCa病例和1,000名筛查的对照病例，对第一阶段确定的前16,420个SNP(加上300个祖先信息标记)和以前的PCa GWASs进行基因分型。最后，我们将从第二阶段的结果(加上300个祖先信息标记)中对500例EO非裔美国人PCa病例和500名来自密歇根大学和JHU的非裔美国人对照样本中的1236个关联最强的SNPs进行基因分型和相关性测试，以评估我们的最新发现在受PCa不成比例影响的第二人群中的重要性。这项研究代表着一个强大而前所未有的机会，可以使用来自两个在PCA研究方面有着长期合作历史的研究团队的特征良好的样本来识别与EO PCA相关的遗传易感变异。公共卫生相关性：2008年，前列腺癌(PCA)是美国男性中最常见的非皮肤相关癌症，估计新增病例186,320例，是癌症相关死亡的第二大原因，估计有28,660例与癌症相关的死亡。识别增加前列腺癌易感性的基因或其他基因组变异将通过提供与前列腺癌发展有关的有价值的生物学数据来影响公众健康。这项研究代表着一个强大而前所未有的机会，可以使用两个特征良好的样本来识别与EO PCA相关的遗传易感变异。

DESCRIPTION (provided by applicant): In 2008, prostate cancer (PCa) was the most commonly diagnosed cancer among men in the United States, with an estimated 186,320 new cases, and the second leading cause of cancer related mortality, with an estimated 28,660 related deaths. Identification of genes or other genomic variants that increase the susceptibility to PCa would impact public health by providing valuable biological data related to the development of PCa. PCa gene discoveries could additionally lead to novel treatment of PCa and provide a valuable additional screening tool for identification of men at increased risk for PCa. Men diagnosed with PCa at an early age are much more likely to die of the disease than men diagnosed later in life, and it has been shown that early-onset (EO) PCa is more likely due to genetic risk factors than later-onset disease. In this proposal, we describe an efficient and powerful multi-stage whole genome-wide association scan (GWAS) for genetic variants that are associated with EO PCa. In the first stage, we propose genotyping 1,000 Caucasian EO PCa cases from the University of Michigan (UM) on ~550,000 SNPs. Differences in observed allele frequencies between these UM EO PCa cases and >3,000 freely available controls from Illumina iControlDB will be assessed to identify a subset of SNPs for follow-up in the second stage. We will genotype the top 16,420 SNPs (plus 300 ancestry informative markers) identified from the first stage and from previous PCa GWASs on 1,250 Caucasian EO PCa cases and 1,000 screened controls from Johns Hopkins University (JHU). Finally, we will genotype, and test for association, our 1,236 most strongly associated SNPs from our second stage results (plus 300 ancestry informative markers) on a sample of 500 EO African American PCa cases and 500 African American controls from UM and JHU to assess the importance of our top findings in a second population that is disproportionably impacted by PCa. This study represents a powerful and unprecedented opportunity to identify genetic susceptibility variants that are associated with EO PCa using well-characterized samples from two investigative teams that have a long history of collaboration in PCa research. PUBLIC HEALTH RELEVANCE: In 2008, prostate cancer (PCa) was the most commonly diagnosed non-skin related cancer among men in the United States, with an estimated 186,320 new cases, and the second leading cause of cancer related mortality, with an estimated 28,660 related deaths. Identification of genes or other genomic variants that increase the susceptibility to PCa would impact public health by providing valuable biological data related to the development of PCa. This study represents a powerful and unprecedented opportunity to identify genetic susceptibility variants that are associated with EO PCa using two well-characterized samples.