Genetics Variants in the Genome Predisposing to Aggressive PCa

基因组中的遗传变异易患侵袭性前列腺癌

基本信息

批准号：
7788795
负责人：
WILLIAM B ISAACS
金额：
$ 62.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2009-03-18 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7788795
关键词：
17q 17q12 17q24.3 8q24 Address Adjuvant Therapy Affect African American Age Alleles American Area Biological Markers Biology Cancer Biology Cancer Patient Characteristics Clinical Cohort Studies Collaborations Core Biopsy Data Databases Development Diagnosis Disease Disease Outcome Disease Progression European Evaluation Family Family history of Frequencies Gene Frequency Gene Proteins Genes Genetic Genetic Markers Genetic Risk Genome Genomics Genotype Gleason Grade for Prostate Cancer Goals Hand Haplotypes Hospitals Individual Indolent Investments Joints Lead Life Linear Regressions Logistic Regressions Machine Learning Malignant Neoplasms Malignant neoplasm of prostate Maps Methods Modeling Molecular Operative Surgical Procedures Organ Pathologic Pathological Staging Pathologist Pathway interactions Patients Pattern Phenotype Physicians Policies Population Population Study Predisposition Prevention strategy Procedures Productivity Property Prostate Publications Publishing Quality of life Radiation Radical Prostatectomy Recruitment Activity Regression Analysis Research Research Design Risk Role Sample Size Sampling Errors Severity of illness Staging Testing Time Tissue Sample Twin Multiple Birth United States National Institutes of Health Universities Variant analytical method base cancer diagnosis cancer genetics cancer risk clinical phenotype cohort data mining data sharing design disease characteristic disease natural history experience follow-up forest gene interaction genetic association genetic linkage genetic linkage analysis genetic variant genome wide association study genome-wide genome-wide analysis genome-wide linkage high risk high risk men improved innovation interest men novel novel strategies patient population public health relevance success therapeutic target tumor tumor progression

项目摘要

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.

描述（由申请人提供）：幸运的是，大多数被诊断出患有前列腺癌（PCA）的男性不会死于疾病，有些被诊断出的男性甚至可能不需要治疗癌症。但是，在另一端，仅在美国，每年约有30,000名男子死于PCA。对于这些后者，PCA的概念显然不适用。了解侵略性PCA（APCA）与惰性PCA（非APCA）的分子基础也许是PCA生物学中最重要的，但转化的问题。我们假设基因组中的多个序列变体赋予APCA的风险，而不是非APCA。利用公开可用的CGEM基因组广泛的关联数据，以及约翰·霍普金斯医院（JHH）的大型和独特的PCA患者人群，我们提出了一项系统的遗传关联研究，以确认，精细地图并更好地表征APCA的遗传风险变异。我们提出了三个具体目的：1）测试与CGEMS研究有关的遗传变异，该研究将APCA与〜3,000个APCA的非APCA区分开，欧洲血统的〜5,000名非APCA患者与JHH的epa apca和5,000名非APCA的基因组区域中的基因组区域和5,000例欧洲祖先相关的基因组区域绘制，并绘制了欧洲祖先的大多数SNP，并绘制了3,000名capca cess的基因组区域。在所有8,000名患者中具有疾病特征的AIM 2中，并且在JHH有后续数据的一部分患者中疾病进展。此外，我们有两个探索性目的：1）在非裔美国人中，欧洲裔美国人和非APCA中包含SNP的区域的精细映射，以及2）测试Gene-Gene相互作用。除了拟议的研究可能根据病因机制提供的明显线索外，这项研究还可能导致鉴定新的靶基因和蛋白质用于治疗以及可能的预防策略。此外，鉴定多种变体可以导致开发测试面板，以改善APCA风险的预测。