Interaction of germline and somatic changes in PCa progression

描述(由申请人提供)：前列腺癌进展中生殖系和体细胞变化的相互作用摘要最近在发现与前列腺癌(PCa)风险相关的生殖系变异方面的成功是令人鼓舞的。然而，这些风险变量是否在PCa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，可能会增加前列腺癌进展的风险。为了验证这一假说，并揭示导致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学标记，我们在该提案中提出了三个具体目标和集成的新颖分析方法。首先，对于胚系变异与前列腺癌风险相关的基因组区域，我们将在96名进展疾病的前列腺癌患者中筛选潜在的胚系CNV、体细胞DNA拷贝数变化和/或甲基化修改。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冰冻肿瘤和正常前列腺组织中提取的DNA样本。其次，我们将在约翰·霍普金斯医院现有的精心设计的研究人群中测试已知的种系PCA风险变量，当与AIM 1中确定的体细胞DNA变化和/或甲基化修改相结合时，是否与PCa进展的风险增加相关，研究人群包括800对进展者和匹配的非进展者。最后，我们将确定其蛋白表达水平与目标2中涉及的遗传和表观遗传学改变相关的基因。这项研究的结果可能会促进我们对PCa进展的病因的理解，并增强现有的方法，以更好地预测哪些PCa患者在诊断时最有可能发展为进展性疾病。对预后较差的PCa患者可加强监测和治疗。公共卫生相关性：这项建议旨在利用几种全球检测方法，确定几种已知的生殖系(PCA)风险变异在我们研究中确定的遗传和体细胞遗传和表观遗传学变化对前列腺癌(PCA)进展的交互影响。已识别的基因可能会促进我们对PCa进展的病因的理解，并增强现有的方法，以更好地预测哪些PCa患者在诊断时最有可能发展为进展性疾病。对预后较差的PCa患者可加强监测和治疗。

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.