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）的男性不会死于这种疾病，有些被诊断出患有前列腺癌的男性甚至不需要治疗。然而，另一方面，仅在美国，每年约有3万男性死于前列腺癌。对于后者，PCa作为一种惰性疾病的概念显然不适用。了解侵袭性前列腺癌（aPCa）与惰性前列腺癌（非aPCa）的分子基础可能是前列腺癌生物学中最重要的基础问题。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。利用公开可用的CGEMS基因组全关联数据，以及约翰霍普金斯医院（JHH）大量独特的PCa患者群体，我们提出了一项系统的遗传关联研究，以确认、精细绘制和更好地表征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异，在JHH的约3000名aPCa和约5000名非aPCa的欧洲血统患者中区分aPCa和非aPCa， 2)在JHH的3000名aPCa和5000名非aPCa的欧洲血统患者中精细绘制涉及Aim 1的snp的基因组区域，以及3)评估Aim 2中发现的最显著snp与所有8000名患者的疾病特征的关联。以及在JHH有随访数据的一部分患者的疾病进展。此外，我们有两个探索性目标：1)精细定位在aPCa中含有在欧洲美国人中显著的snp的区域，在非裔美国人中含有非aPCa的区域，以及2)检测基因-基因相互作用。除了该研究可能在病因机制方面提供明显的线索外，该研究还可能导致鉴定新的靶基因和蛋白用于治疗和可能的预防策略。此外，多种变异的识别可以导致测试小组的发展，这可能会提高对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.