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，也是世界范围内日益增长的负担，但对前列腺癌（PCa）易感性的分子机制的理解仍然难以捉摸，特别是关于临床相关的侵袭性前列腺癌的遗传风险。分离分析和双胞胎研究与PCa风险的重要遗传成分一致，为美国和欧洲的研究小组进行的PCa家族连锁分析提供了强有力的基础，并暗示许多不同的位点可能包含PCa易感基因。这些初步研究强调家族性前列腺癌具有广泛的异质性。为了解决和克服这种异质性给前列腺癌易感基因定位和鉴定带来的困难，国际前列腺癌遗传学协会（ICPCG）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2600多个前列腺癌家族的DNA样本，包括有3个或更多成员患有侵袭性前列腺癌的家庭。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，包括涉及易感基因鉴定，遗传异质性，前列腺癌家族中其他癌症的分离，以及PCa基因被鉴定后的基因频率和外显率。在本提案中，我们寻求进一步开发和利用ICPCG的综合资源，进行系统分析，以识别和表征前列腺癌易感基因。具体而言，我们建议：1)结合来自2000个前列腺癌家族（包括110多个非洲裔美国人前列腺癌家族）的全基因组扫描连锁结果，确定最有可能携带前列腺癌易感基因的区域，特别强调诊断年龄早、受影响个体数量多、临床侵袭性疾病特征多的家族亚群；2)对这些区域进行精细映射，缩小感兴趣区域（ROI）；3)进行密集SNP基因分型，识别和评估与PCa风险相关的候选基因，缩小ROI；4)在独立病例对照人群中确认并进一步表征与PCa风险相关的snp；5)在未观察到关联的区域中寻找具有关联的罕见变异。预计这一综合资源及其持续分析所带来的研究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., and a growing burden worldwide, an understanding of the molecular mechanisms underlying susceptibility for prostate cancer (PCa) remains elusive, particularly with respect to inherited risk for clinically relevant, aggressive PCa. Segregation analyses and twin studies are consistent with an important genetic component for PCa risk, providing a strong basis for linkage analyses of PCa families undertaken by research groups in the U.S. and Europe and resulting in implication of many different loci as potentially harboring PCa susceptibility genes. These initial studies emphasize the extensive heterogeneity that characterizes familial PCa. To address and overcome the difficulties that this heterogeneity presents for PCa susceptibility gene mapping and identification, the International Consortium for Prostate Cancer Genetics (ICPCG) was established. This 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 2600 prostate cancer families, including families with 3 or more members affected with aggressive prostate cancer. The size and diversity of this consortium make it ideally suited to address questions in molecular genetics of prostate cancer, including those involving susceptibility gene identification, genetic heterogeneity, other cancers segregating in prostate cancer families, and gene frequency and penetrance of PCa genes once they are identified. In this proposal, we seek the further development and use of the combined resources of the ICPCG to perform systematic analyses to identify and characterize prostate cancer susceptibility genes. Specifically, we propose to: 1) Define the most likely regions harboring prostate cancer susceptibility genes by combining genome wide scan linkage results from -2000 prostate cancer families (including over 110 African American PCa families), with special emphasis on subsets of families with early age at diagnosis, large numbers of affected individuals, and multiple cases with features of clinically aggressive disease; 2) Perform fine mapping in these regions to narrow the region of interest (ROI); 3) Perform dense SNP genotyping to identify and evaluate candidate genes associated with PCa risk in narrowed ROI; 4) Confirm and further characterize any SNPs associated with PCa risk in independent case-control populations; 5) Search for rare variants accounting for linkage in regions where no association is observed. It is anticipated that this combined resource and the studies made possible by its continued analysis will provide an unprecedented opportunity to characterize and unravel the complexities of genetic susceptibility for this common disease.