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

描述（由申请人提供）：2008年，前列腺癌（PCa）是美国男性中最常见的诊断癌症，估计有186,320例新病例，也是癌症相关死亡的第二大原因，估计有28,660例相关死亡。鉴定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方法，并为识别前列腺癌风险增加的男性提供有价值的额外筛查工具。早期诊断为前列腺癌的男性比晚期诊断为前列腺癌的男性更有可能死于该疾病，并且已经表明早发性（EO）前列腺癌更有可能是由于遗传风险因素而不是晚发性疾病。在这个提议中，我们描述了一个高效和强大的多阶段全基因组关联扫描（GWAS），用于与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EO PCa病例进行约55万个snp的基因分型。将评估这些UM EO PCa病例与Illumina iControlDB中免费提供的1000 000例对照之间观察到的等位基因频率的差异，以确定一个snp子集，以便在第二阶段进行随访。我们将对来自约翰霍普金斯大学（JHU）的1,250例高加索EO型PCa病例和1,000例筛选对照的第一阶段和以前的PCa GWASs中鉴定出的前16,420个snp（加上300个祖先信息标记）进行基因分型。最后，我们将对500个EO非裔美国人PCa病例和500个来自UM和JHU的非裔美国人对照样本的第二阶段结果（加上300个祖先信息标记）中的1236个最强烈相关的snp进行基因分型和相关性测试，以评估我们的主要发现在受PCa比例影响的第二群体中的重要性。这项研究提供了一个强大的、前所未有的机会，可以利用两个在前列腺癌研究方面有着长期合作历史的调查团队的良好特征样本，来识别与EO前列腺癌相关的遗传易感性变异。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，估计有186,320例新病例，也是癌症相关死亡的第二大原因，估计有28,660例相关死亡。鉴定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。这项研究代表了一个强大的和前所未有的机会，以确定遗传易感性变异相关的EO PCa使用两个良好的特征样本。

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.