Interaction of germline and somatic changes in PCa progression

摘要最近发现与前列腺癌（PCa）风险相关的生殖系变异的成功是令人鼓舞的。然而，这些风险变异是否在前列腺癌进展中起作用尚不清楚。了解与前列腺癌进展相关的因素将对该疾病的管理和治疗产生重大影响。我们假设生殖系风险变异，结合体细胞遗传和表观遗传变化可能增加前列腺癌进展的风险。为了验证这一假设，并揭示前列腺癌进展和不良临床结果的复杂机制的遗传和表观遗传标记，我们在本提案中提出了三个具体目标，采用综合和新颖的分析方法。首先，对于生殖系变异与PCa风险相关的基因组区域，我们将在96名疾病进展的PCa患者中筛选潜在的生殖系CNVs、体细胞DNA拷贝数变化和/或甲基化修饰。几种新的全球DNA拷贝数和甲基化检测方法将被用于检测从冷冻肿瘤和正常前列腺组织分离的DNA样本。其次，我们将测试已知的种系PCa风险变异，当结合Aim 1中确定的体细胞DNA变化和/或甲基化修饰时，是否与约翰霍普金斯医院现有的设计良好的研究人群（包括800对进展者和匹配的非进展者）中PCa进展风险增加有关。最后，我们将确定其蛋白表达水平与Aim 2中涉及的遗传和表观遗传改变相关的基因。这项研究的结果可能会促进我们对前列腺癌进展的病因学的理解，并增强现有的方法，以更好地预测哪些前列腺癌患者在诊断时最有可能发展为疾病进展。预后较差的前列腺癌患者可接受强化监测和治疗。公共卫生相关性：本提案旨在使用几种全球检测方法，确定我们研究中发现的几种已知生殖系（PCa）风险变异遗传、体细胞遗传和表观遗传变化对前列腺癌（PCa）进展的相互作用。所鉴定的基因可能会促进我们对前列腺癌进展的病因学的理解，并增强当前的方法，以更好地预测哪些前列腺癌患者在诊断时最有可能发展为疾病进展。预后较差的前列腺癌患者可接受强化监测和治疗。

DESCRIPTION (provided by applicant): Interaction of germline and somatic changes in PCa progression Abstract Recent successes in discovering germline variants associated with prostate cancer (PCa) risk is encouraging. However, whether these risk variants play role in PCa progression is unclear. Understanding factors associated with the progression of PCa will have a significant impact on management and treatment of the disease. We hypothesize that germline risk variants, combined with somatic genetic and epigenetic changes may increase the risk of prostate cancer progression. To test this hypothesis and to uncover the genetic and epigenetic markers of the complex mechanisms underlining the progression and poor clinical outcome of PCa, we present three specific aims with integrated and novel analytic approaches in this proposal. First, for the genomic regions where germline variants are associated with PCa risk, we will screen for potential germline CNVs, somatic DNA copy number changes and/or methylation modifications among 96 PCa patients who have developed progressed disease. Several novel global DNA copy number and methylation detection methods will be employed to examine DNA samples isolated from frozen tumor and normal prostate tissues. Secondly, we will test whether known germline PCa risk variants, when combined with somatic DNA changes and/or methylation modifications identified in Aim 1, are associated with increased risk for PCa progression in an existing and well-designed study population from Johns Hopkins Hospital, including 800 pairs of progressors and matched non-progressors. Finally, we will identify genes whose protein expression levels are associated with genetic and epigenetic alterations that are implicated in Aim 2. The results of this study may advance our understanding on the etiology of PCa progression and augment current methods to better predict which PCa patients are most likely to develop progressed disease at the time of diagnosis. The PCa patients with poor prognosis can receive intensive monitoring and treatment. PUBLIC HEALTH RELEVANCE: This proposal intends to identify interaction effects on prostate cancer (PCa) progression for several known germline (PCa) risk variants genetic and somatic genetic and epigenetic changes identified in our study, using several global detection methods. The identified genes may advance our understanding on the etiology of PCa progression and augment current methods to better predict which PCa patients are most likely to develop progressed disease at the time of diagnosis. The PCa patients with poor prognosis can receive intensive monitoring and treatment.