Interaction of germline and somatic changes in PCa progression

PCa 进展中种系和体细胞变化的相互作用

基本信息

批准号：
8193209
负责人：
WILLIAM B ISAACS
金额：
$ 35.64万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8193209
关键词：
10q11 11q13 17q12 17q24 7p15 7q21 8q24 9q33 Affect Analysis of Variance Area Biochemical Biological Biological Assay Biology Biopsy Cancer Biology Cancer Patient Cessation of life Chromosomes Classification Clinical Collaborations Complex DNA DNA Methylation DNA copy number Data Data Quality Detection Development Diagnosis Discipline Disease Disease Progression Distant Metastasis Epigenetic Process Etiology Failure Formalin Freezing Funding Gene Expression Gene Mutation Genes Genetic Genome Genomics Genotype Gleason Grade for Prostate Cancer Goals Health Hospitals Human Immunohistochemistry Knowledge Lead Malignant Neoplasms Malignant neoplasm of prostate Measures Methods Methylation Modification Molecular Monitor Mutation Operative Surgical Procedures Outcome Paraffin Embedding Pathologic Pathology Patients Phenotype Play Population Population Study Positioning Attribute Prostate Prostatic Neoplasms Race Radical Prostatectomy Recurrence Reporting Research Research Design Resolution Risk Risk Factors Role Sampling Single Nucleotide Polymorphism Staging Survival Analysis TNM Testing The Sun Time Tissues Tumor-Derived Variant abstracting base cancer diagnosis cancer genetics cancer risk cost effective forest genetic epidemiology genetic variant genome wide association study genome-wide improved innovation men novel outcome forecast protein expression success therapy development tumor tumor progression urologic

项目摘要

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.

描述（由申请人提供）：在发现与前列腺癌（PCA）风险相关的种系变异方面，种系的相互作用和PCA进展中的躯体变化摘要。但是，这些风险变异是否在PCA进展中起着作用，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。我们假设种系风险变异与体细胞遗传和表观遗传变化相结合可能会增加前列腺癌进展的风险。为了检验这一假设并揭示了强调PCA进展和临床结果不佳的复杂机制的遗传和表观遗传标记，我们在该提案中采用了综合和新颖的分析方法提出了三个特定目标。首先，对于与PCA风险相关的种系变异的基因组区域，我们将筛选潜在的生殖线CNV，在发生发展进展疾病的96名PCA患者中的体细胞DNA拷贝数变化和/或甲基化修饰。将采用几种新型的全局DNA拷贝数和甲基化检测方法来检查从冷冻肿瘤和正常前列腺组织中分离出来的DNA样品。其次，我们将测试AIM 1中已知的生殖线PCA风险变异与体细胞DNA变化和/或甲基化修饰相结合，与现有且精心设计的研究人群的PCA进展风险增加有关，包括800对进步者和非培训者，包括800对。最后，我们将确定其蛋白质表达水平与AIM 2有关的蛋白质表达水平与遗传和表观遗传改变有关的基因。这项研究的结果可能会促进我们对PCA进展的病因的理解，并增强当前方法，以更好地预测哪些PCA患者最有可能在诊断时发展进展的疾病。预后不良的PCA患者可以接受密集的监测和治疗。公共卫生相关性：该提案旨在使用几种全球检测方法来确定几种已知种系（PCA）风险变异的相互作用对几种已知种系（PCA）风险变异的遗传和体细胞遗传和表观遗传变化的影响。鉴定的基因可能会提高我们对PCA进展的病因和增强当前方法的理解，以更好地预测哪些PCA患者在诊断时最有可能发展进展的疾病。预后不良的PCA患者可以接受密集的监测和治疗。