Genetics Variants in the Genome Predisposing to Aggressive PCa

描述（由申请人提供）：幸运的是，大多数被诊断患有前列腺癌（PCa）的男性不会死于他们的疾病，一些被诊断的男性甚至可能不需要治疗他们的癌症。然而，在另一端，仅在美国每年就有约30，000名男性死于PCa。对于后者，PCa作为惰性疾病的概念显然不适用。了解侵袭性PCa（aPCa）与惰性PCa（non-aPCa）的分子基础可能是PCa生物学中最重要的基础但翻译问题。我们假设基因组中的多个序列变异赋予aPCa风险，而不是非aPCa。利用公开可用的CGEMS全基因组关联数据，以及约翰霍普金斯医院（JHH）的大型和独特的PCa患者人群，我们提出了一个系统的遗传关联研究，以确认，精细映射，并更好地表征aPCa的遗传风险变异。我们提出三个具体目标：1）测试CGEMS研究中涉及的遗传变体，其在来自JHH的欧洲血统的约3，000名aPCa和约5，000名非aPCa患者中区分aPCa与非aPCa，2）在来自JHH的欧洲血统的3，000名aPCa和约5，000名非aPCa患者中精细绘制涉及Aim 1的SNP的基因组区域，和3）评估Aim 2中发现的最重要的SNP与所有8，000名患者的疾病特征的关联，以及与在JHH有随访数据的患者亚组的疾病进展的关联。此外，我们还有两个探索性目标：1）在aPCa和非aPCa的欧洲裔美国人中精细定位含有显著SNP的区域，以及2）检测基因-基因相互作用。除了拟议的研究可能在病因机制方面提供的明显线索外，这项研究还可能导致识别新的靶基因和蛋白质用于治疗和可能的预防策略。此外，多种变异的鉴定可导致开发可改善aPCa风险预测的检测组。

DESCRIPTION (provided by applicant): Fortunately, most men diagnosed with prostate cancer (PCa) will not die from their disease, and some men diagnosed may not even require treatment for their cancers. However, on the other end of the spectrum, ~30,000 men annually die from PCa in the US alone. For these latter men, the concept of PCa as an indolent disease obviously does not apply. Understanding the molecular basis of aggressive PCa (aPCa) vs. indolent PCa (non-aPCa) is perhaps the most important basic, yet translational question in PCa biology. We hypothesize that multiple sequence variants in the genome confer risk to aPCa but not to non-aPCa. Taking advantage of the publicly available CGEMS genome wide association data, as well as the large and unique PCa patient population at Johns Hopkins Hospital (JHH), we propose a systematic genetic association study to confirm, fine map, and better characterize genetic risk variants for aPCa. We propose three specific aims: 1)Test the genetic variants implicated in the CGEMS study that distinguish aPCa from non-aPCa among ~3,000 aPCa and ~5,000 non-aPCa patients of European ancestry from the JHH, 2) Fine map the genomic regions for the SNPs implicated in Aim 1 among 3,000 aPCa and 5,000 non-aPCa patients of European ancestry from the JHH, and 3) Assess the association of the most significant SNPs found in Aim 2 with disease characteristics in all 8,000 patients, and with disease progression in a subset of patients that have follow-up data at JHH. In addition, we have two exploratory aims: 1) fine mapping of regions containing SNPs significant in European Americans in aPCa and non-aPCa in African Americans, and 2) testing for gene-gene interaction. Besides the obvious clues that the proposed research may provide in terms of etiologic mechanisms, this study may also lead to identification of new target genes and proteins for therapy and possible preventive strategies. Furthermore, the identification of multiple variants can lead to the development of a test panel that may improve prediction of aPCa risk.