Defining Genetic Risk Factors for Brothers of Men with Prostate Cancer

确定患有前列腺癌的男性兄弟的遗传风险因素

基本信息

批准号：
7468645
负责人：
KATHLEEN A COONEY
金额：
$ 27.04万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7468645
关键词：
17q21 Accounting Affect Age Alleles Amino Acid Substitution Arginine BRCA1 gene Brothers CXCL12 gene CXCR4 gene CYP17A1 gene Cancer Family Cancer-Predisposing Gene Candidate Disease Gene Case-Control Studies Chromosomes Codon Nucleotides Collaborations Conflict (Psychology)Crohn&apos s disease DNA Data Diagnosis Disease Elevation Enrollment Exons FHIT gene Family Family history of Family member Funding Gene Frequency Genes Genetic Predisposition to Disease Genetic Variation Genome Glutamine Goals Human Inherited Insulin-Dependent Diabetes Mellitus International Literature Malignant Neoplasms Malignant neoplasm of prostate Methods Michigan Minor Molecular Mutation Nature Nucleotides Numbers Oncogenes Pathway interactions Penetrance Phenocopy Predisposition Principal Investigator Progress Reports Rate Reporting Reproduction spores Research Research Design Resources Risk Factors Sampling Scanning Screening procedure Second Degree Relative Siblings Single Nucleotide Polymorphism Staging Testing Time Universities Validation Variant base cancer genetics cancer risk design early onset follow-up genetic association genetic linkage analysis genetic risk factor genetic variant genome wide association study genome-wide linkage improved men novel programs

项目摘要

While family history is an important risk factor for prostate cancer, localization of highly penetrant prostate cancer susceptibility genes using traditional linkage analysis has been challenging. In this SPORE project, we used our ongoing study of hereditary prostate cancer study (the University of Michigan Prostate Cancer Genetics Project or PCGP) to identify a set of sibling pairs discordant for prostate cancer. These siblings can be used to implicate genes of modest penetrance using family-based association methods. Since the sibships are derived from families with early-onset and/or hereditary prostate cancer, they are relatively enriched for genetic susceptibility factors. During the first five years of funding, we have established the discordant sibling pair (DSP) project as a resource for characterizing germline variants associated with prostate cancer. To date, we have studied 14 candidate genes and have shown that single nucleotide DOlymorphisms (SNPs) in CYP17, BRCA1, FHIT, SDF1, CXCR4, and AMACRare significantly associated with prostate cancer. Our most compelling association finding involves a glutamine-to-arginine substitution at codon 356 (Gln356Arg) in exon 11 of the BRCA1 gene that accounts for some (but not all) of our prior vidence of prostate cancer linkage to chromosome 17q21 in a PCGP genome-wide linkage scan. Nonsynonymous SNPs (nsSNPs), such as BRCA1 Gln356Arg, result in single amino acid substitutions and have been shown to account for many of the genetic changes that influence Mendelian disorders. In this SPORE renewal project, we propose a genome-wide approach focusing on nsSNPs in known genes, including many genes previously implicated in cancer. This proposed genome-wide approach has the advantage of testing for variants that are likely to be causative and has been successfully used to identify novel candidate loci for type 1 diabetes and Crohn disease. To test the hypothesis that common nsSNPs in BRCA1 and other candidate genes are associated with prostate cancer, the following two Specific Aims are proposed: Specific Aim 1: Develop our new, formal collaboration with the SPORE program at Johns Hopkins University to follow-up and generalize significant prostate cancer associations, including our previously reported prostate cancer association with BRCA1 Gln356Arg. Specific Aim 2. Complete a replication-based genome-wide association study of early-onset and familial prostate cancer using more than 11,500 nsSNPs that cover approximately 6,500 known human genes, including a disproportionate number in cancer-related pathways.

虽然家族史是前列腺癌的重要危险因素，但高渗透性前列腺的定位使用传统的连锁分析来分析癌症易感性基因一直具有挑战性。在这个 SPORE 项目中，我们使用了我们正在进行的遗传性前列腺癌研究（密歇根大学前列腺癌遗传学项目（PCGP）来识别一组与前列腺癌不一致的兄弟姐妹对。这对兄妹可用于使用基于家族的关联方法来暗示具有适度外显率的基因。自从同胞关系源自患有早发性和/或遗传性前列腺癌的家庭，他们相对来说丰富的遗传易感因素。在资助的头五年中，我们建立了不一致兄弟对 (DSP) 项目作为表征与相关种系变异相关的资源前列腺癌。迄今为止，我们已经研究了 14 个候选基因，并表明单核苷酸 CYP17、BRCA1、FHIT、SDF1、CXCR4 和 AMACR 中的 DO 多态性 (SNP) 显着相关患有前列腺癌。我们最引人注目的关联发现涉及谷氨酰胺到精氨酸的替代 BRCA1 基因外显子 11 的密码子 356 (Gln356Arg) 解释了我们之前的一些（但不是全部） PCGP 全基因组连锁扫描中前列腺癌与染色体 17q21 连锁的证据。非同义 SNP (nsSNP)，例如 BRCA1 Gln356Arg，会导致单个氨基酸取代并具有已被证明可以解释许多影响孟德尔疾病的基因变化。在这个孢子里更新项目中，我们提出了一种全基因组方法，重点关注已知基因中的 nsSNP，包括许多以前与癌症有关的基因。这种提议的全基因组方法具有测试的优点对于可能致病的变异，并已成功用于识别新的候选基因座 1 型糖尿病和克罗恩病。检验 BRCA1 和其他候选基因中常见的 nsSNP 与针对前列腺癌，提出以下两个具体目标：具体目标 1：与约翰霍普金斯大学的 SPORE 项目开展新的正式合作大学追踪并概括重要的前列腺癌关联，包括我们之前的研究报道了前列腺癌与 BRCA1 Gln356Arg 的关联。具体目标 2. 完成早发型和家族性基于复制的全基因组关联研究前列腺癌使用超过 11,500 个 nsSNP，涵盖约 6,500 个已知人类基因，其中包括不成比例的癌症相关途径。