Interaction of germline and somatic changes in PCa progression

描述（由申请人提供）：PCa进展中生殖细胞和体细胞变化的相互作用摘要最近在发现与前列腺癌（PCa）风险相关的生殖细胞变异方面的成功令人鼓舞。然而，这些风险变异是否在PCa进展中发挥作用尚不清楚。了解与PCa进展相关的因素将对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会增加前列腺癌进展的风险。为了验证这一假设，并揭示复杂机制的遗传和表观遗传标记，强调PCa的进展和不良的临床结果，我们提出了三个具体的目标与综合和新的分析方法在这个建议。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名已发展为疾病进展的PCa患者中筛选潜在的生殖系CNV、体细胞DNA拷贝数变化和/或甲基化修饰。几种新的全局DNA拷贝数和甲基化检测方法将被用于检测从冷冻的肿瘤和正常前列腺组织中分离的DNA样品。其次，我们将在来自约翰霍普金斯医院的现有和精心设计的研究人群（包括800对进展者和匹配的非进展者）中，测试已知的生殖系PCa风险变体，当与目标1中鉴定的体细胞DNA变化和/或甲基化修饰组合时，是否与PCa进展风险增加相关。最后，我们将确定其蛋白质表达水平与目标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PCa进展的病因学的理解，并增强目前的方法，以更好地预测哪些PCa患者在诊断时最有可能发展为疾病进展。对预后差的PCa患者应加强监测和治疗。公共卫生相关性：该提案旨在使用几种全球检测方法，确定我们研究中确定的几种已知生殖系（PCa）风险变异遗传和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。这些发现的基因可能会促进我们对PCa进展病因的理解，并增强目前的方法，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。对预后差的PCa患者应加强监测和治疗。

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.