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）是美国男性中最常诊断的癌症，估计有186，320例新发病例，并且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PCa易感性的基因或其他基因组变体将通过提供与PCa发展相关的有价值的生物学数据来影响公共卫生。PCa基因的发现还可能导致PCa的新治疗方法，并为识别PCa风险增加的男性提供有价值的额外筛选工具。在早期被诊断出患有PCa的男性比在生命后期被诊断出的男性更有可能死于该疾病，并且已经表明早发性（EO）PCa更可能是由于遗传风险因素而不是迟发性疾病。在这个建议中，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）的遗传变异与EO PCa。在第一阶段，我们建议对来自密歇根大学（UM）的1，000例高加索EO PCa病例进行约550，000个SNP的基因分型。将评估这些UM EO PCa病例与来自Illumina iControlDB的> 3，000个免费可用对照之间观察到的等位基因频率的差异，以鉴定SNP子集用于第二阶段的随访。我们将对来自约翰霍普金斯大学（JHU）的1，250例白人EO PCa病例和1，000例筛选对照的第一阶段和既往PCa GWAS中鉴定的前16，420个SNP（加上300个祖先信息标记）进行基因分型。最后，我们将对来自UM和JHU的500例EO非裔美国人PCa病例和500例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）的1，236个最强相关的SNP进行基因分型和相关性测试，以评估我们在第二人群中的重要发现的重要性，该人群受到PCa的影响。这项研究代表了一个强大的和前所未有的机会，以确定与EO PCa相关的遗传易感性变异，使用来自两个在PCa研究方面有着长期合作历史的调查团队的充分表征的样本。公共卫生相关性：2008年，前列腺癌（PCa）是美国男性中最常诊断的非皮肤相关癌症，估计有186，320例新发病例，并且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PCa易感性的基因或其他基因组变体将通过提供与PCa发展相关的有价值的生物学数据来影响公共卫生。本研究代表了一个强大的和前所未有的机会，以确定与EO PCa相关的遗传易感性变异，使用两个良好的表征样本。

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.