Defining Genetic Risk Factors for Brothers of Men with Prostate Cancer

虽然家族史是前列腺癌的一个重要危险因素，但高度渗透性前列腺的定位 使用传统的连锁分析癌症易感基因是具有挑战性的。在这个SPORE项目中， 我们使用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研究）， 遗传学项目或PCGP），以确定一组同胞对不一致的前列腺癌。这对兄妹 可用于使用基于家族的关联方法来推断适度遗传的基因。以来 兄弟姐妹来自早发性和/或遗传性前列腺癌的家庭，他们相对 富含遗传易感因子。在最初的五年里，我们建立了 不一致同胞对（DSP）项目作为一个资源，用于表征与 前列腺癌到目前为止，我们已经研究了14个候选基因，并表明单核苷酸 CYP 17、BRCA 1、FHIT、SDF 1、CXCR 4和AMAC中的多态性（SNP）显著相关。 前列腺癌我们最令人信服的关联发现涉及谷氨酰胺到精氨酸的取代 BRCA 1基因外显子11的密码子356（Gln 356 Arg），这解释了我们先前的一些（但不是全部） PCGP全基因组连锁扫描中前列腺癌与染色体17 q21连锁的证据。非同义 SNP（nsSNP），如BRCA 1 Gln 356 Arg，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遗传变化。在这个孢子 更新项目，我们提出了一个全基因组的方法，专注于已知基因中的nsSNPs，包括许多 以前与癌症有关的基因。这种提出的全基因组方法的优点是测试 对于可能是致病性的变异，并已成功地用于鉴定新的候选基因座， 1型糖尿病和克罗恩病。 为了验证BRCA 1和其他候选基因中常见的nsSNPs与以下假设相关： 前列腺癌，提出了以下两个具体目标： 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 大学随访和推广重要的前列腺癌协会，包括我们以前的研究。 报告前列腺癌与BRCA 1 Gln 356 Arg相关。 具体目标2。完成一项基于复制的早发性和家族性 前列腺癌使用超过11，500个nsSNP，覆盖大约6，500个已知的人类基因， 包括癌症相关途径中不成比例的数量。

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.