Prostate Cancer Susceptibility: The ICPCG Study

描述（由申请人提供）：尽管前列腺癌是美国男性中最常见的癌症，但对前列腺癌易感性的分子机制的理解仍然难以捉摸。分离分析表明显性高风险前列腺癌易感等位基因的存在，这可能占所有前列腺癌病例的10%。尽管遗传性前列腺癌（HPC）的连锁分析由于许多障碍而变得复杂，但美国和欧洲的研究小组已经发现至少有6个位点含有HPC基因。这些初步研究强调了HPC的广泛异质性。为了解决和克服这种异质性给HPC基因定位和鉴定带来的困难，国际前列腺癌遗传学协会成立了。该联盟由来自北美、欧洲和澳大利亚7个不同国家的20多个机构的研究人员组成，他们在这一领域都有广泛的、正在进行的研究项目。这个小组一起收集了1700多个前列腺癌家族的DNA样本，每个家族至少有三个一级亲属患有前列腺癌，这使得这个综合资源独一无二，也是迄今为止同类资源中最大的一个。该联盟的规模和多样性使其非常适合解决前列腺癌的分子遗传学问题，包括涉及遗传异质性，前列腺癌家族中其他癌症的分离，以及克隆后HPC的基因频率和外显率。在本提案中，要求资金支持ICPCG联合资源的开发和使用，以进行系统分析，以确定和表征前列腺癌易感位点。具体来说，我们建议：1)分析完整的家族收集，寻找先前鉴定的位点（例如1p36, 1q43-43, 17p11, 20q13, Xq27-28）和在资助期间鉴定的新位点的连锁证据；2)根据临床和家庭参数进行家庭分层后的联合连锁分析，以检验确定的家庭亚群中的连锁；3)开发新的方法来优化和促进对这个独特数据集的分析。预计这一综合资源及其开发使研究成为可能，将提供一个前所未有的机会，以表征和揭示这一常见疾病遗传易感性的复杂性。

DESCRIPTION (provided by applicant): Despite being the most common cancer diagnosed in men in the U.S., an understanding of the molecular mechanisms underlying susceptibility for prostate cancer remains elusive. Segregation analyses suggest the existence of dominant high risk prostate cancer susceptibility alleles, which may account for up to 10 percent of all prostate cancer cases. Although linkage analysis of hereditary prostate cancer (HPC) is complicated by a number of barriers, research groups in the U.S. and Europe have implicated at least six loci as harboring HPC genes. These initial studies emphasize the extensive heterogeneity that characterizes HPC. To address and overcome the difficulties that this heterogeneity presents for HPC gene mapping and identification, the International Consortium for Prostate Cancer Genetics was established. The consortium consists of researchers from over 20 institutions in 7 different countries in North America, Europe, and Australia, all of whom have extensive, ongoing research programs in this area. Together, this group has collected DNA samples from over 1700 prostate cancer families, each having at least three first degree relatives affected with prostate cancer, making this combined resource unique and by far the largest one of its kind. The size and diversity of this consortium make it ideally suited to address questions in molecular genetics of prostate cancer, including those involving genetic heterogeneity, other cancers segregating in prostate cancer families, and gene frequency and penetrance of HPC once they are cloned. In this proposal, funds are requested to support the development and use of the combined resources of the ICPCG to perform systematic analyses to identify and characterize prostate cancer susceptibility loci. Specifically, we propose to : 1) analyze the complete family collection for evidence of linkage at both previously identified loci (e.g. 1p36, 1q43-43, 17p11, 20q13, Xq27-28) and novel loci identified over the course of the funding period; 2) carry out combined linkage analyses following stratification of families based upon clinical and family parameters to examine linkage in defined subsets of families; 3) develop new methodologies to optimize and facilitate the analysis of this unique dataset. It is anticipated that this combined resource and the studies made possible by its development will provide an unprecedented opportunity to characterize and unravel the complexities of genetic susceptibility for this common disease.