Defining Genetic Risk Factors for Brothers of Men with Prostate Cancer

虽然家族史是前列腺癌的重要危险因素，但高穿透性前列腺癌的定位 用传统的连锁分析方法分析癌症易感基因一直具有挑战性。在这个孢子项目中， 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 遗传学项目或PCGP)，以确定一组不一致的兄弟姐妹对前列腺癌。这些兄弟姐妹 可以用来通过基于家庭的关联方法来推断适度外显的基因。自.以来 兄弟姐妹关系来自早发性和/或遗传性前列腺癌家族，他们相对 富含遗传易感因素。在最初五年的资助中，我们建立了 不一致兄弟姐妹对(DSP)项目，作为表征与 前列腺癌。到目前为止，我们已经研究了14个候选基因，并证明了单核苷酸 CYP17、BRCA1、FHIT、SDF1、CXCR4和AMACR基因的单核苷酸多态性(SNPs)显著相关 患有前列腺癌。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 在BRCA1基因外显子11的第356密码子(Gln356Arg)，它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连锁的可能性。非同义词 单核苷酸多态(NsSNPs)，如BRCA1 Gln356Arg，导致单一氨基酸替换并具有 已被证明是影响孟德尔病症的许多基因变化的原因。在这个孢子里 更新计划，我们提出了一种全基因组的方法，专注于已知基因中的nsSNPs，包括许多 此前与癌症有关的基因。这一建议的全基因组方法具有测试的优势 对于可能是致病原因的变体，并已成功地用于识别新的候选基因座 1型糖尿病和克罗恩病。 为了验证BRCA1和其他候选基因中常见的nsSNPs与 关于前列腺癌，提出了以下两个具体目标： 具体目标1：发展我们与约翰霍普金斯大学孢子计划的新的正式合作 大学跟进和推广重要的前列腺癌关联，包括我们以前的 已报道前列腺癌与BRCA1 Gln356Arg有关。 具体目标2.完成一项基于复制的早发性和家族性全基因组关联研究 使用了超过11500个nsSNPs，覆盖了大约6500个已知的人类基因， 包括与癌症相关的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.