Genetics Variants in the Genome Predisposing to Aggressive PCa

描述(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，一些被诊断为前列腺癌的男性甚至可能不需要治疗他们的癌症。然而，另一方面，仅在美国，每年就有约30,000名男性死于PCA。对于这些后来者来说，将前列腺癌视为一种惰性疾病的概念显然不适用。了解攻击性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本问题，但也是翻译问题。我们假设基因组中的多个序列变异会给APCA带来风险，但不会给非APCA带来风险。利用可公开获得的CGEMS全基因组关联数据，以及约翰霍普金斯医院(JHH)庞大而独特的PCa患者群体，我们提出了一项系统的遗传关联研究，以确认、精细定位和更好地描述APCA的遗传风险变异。我们提出了三个具体目标：1)测试CGEMS研究中涉及的基因变异，以区分来自JHH的~3,000名APCA和~5,000名欧洲血统的非APCA患者中的APCA和非APCA；2)精细绘制JHH的3,000名APCA和5,000名欧洲血统的非APCA患者中AIM 1涉及的SNPs的基因组区域；以及3)评估在AIM 2中发现的最重要的SNPs与所有8,000名患者的疾病特征以及在JHH有后续数据的患者子集中的疾病进展的关联。此外，我们还有两个探索性目标：1)在APCA中精细定位在欧洲裔美国人中显著的SNPs区域，在非裔美国人中找到非APCA中显著的SNP区域，以及2)检测基因-基因交互作用。除了提出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向基因和蛋白用于治疗和可能的预防策略。此外，多个变异的识别可以导致开发一个测试小组，该小组可能会改善对APCA风险的预测。

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.