Genetic Analysis of Hereditary Prostate Cancer Families

描述（由申请人提供）：认识到前列腺癌在家庭内聚集，导致许多研究小组，包括我们自己的收集家庭与多个前列腺癌病例的连锁研究。不幸的是，尽管收集和分析了大量的这样的家庭，主要基因，有助于遗传前列腺癌的易感性一直难以充分表征。至少有八个位点已被提出，现在需要进一步的研究，以确定最重要的临床前列腺癌易感基因。 密歇根大学前列腺癌遗传学项目（PCGP）成立于1995年，是一项基于家族的遗传性前列腺癌易感性研究。最近完成了全基因组连锁扫描，使用176个多重PCGP家族，其中涉及几个新的基因组区域进行进一步的研究。前列腺癌连锁的最有力证据是在邻近BRCA 1基因的17号染色体上。BRCA 1基因的突变已被证明会增加女性患乳腺癌和卵巢癌以及男性患前列腺癌的风险，但BRCA 1突变以前尚未在前列腺癌家族中发现。 为了进一步表征BRCA 1在遗传性前列腺癌中的作用，并确定其他前列腺癌易感基因及其相关临床综合征，提出了以下三个具体目标： 1)评估乳腺癌基因BRCA 1作为PCGP家族中前列腺癌易感基因的作用，2）定位和表征PCGP家族中的候选前列腺癌易感基因，3）鉴定特异性影响临床侵袭性前列腺癌风险的前列腺癌易感基因。这些目标的完成将提高我们对使男性易患前列腺癌的基因以及与特定基因突变相关的临床综合征的理解。最终，这些信息可能具有临床实用性，以确定那些可能受益于早期检测和/或化学预防策略的前列腺癌风险最高的男性。

DESCRIPTION (provided by applicant): The recognition that prostate cancer clusters within families has led many research teams including our own to collect families with multiple cases of prostate cancer for linkage studies. Unfortunately, despite the collection and analysis of a large number of such families, the major genes that contribute to inherit prostate cancer susceptibility have been difficult to fully characterize. At least eight loci have been proposed and further studies are now required to determine the most clinically important prostate cancer predisposition genes. The University of Michigan Prostate Cancer Genetics Project (PCGP) was established in 1995 as a family based study of inherited prostate cancer susceptibility. A genome wide linkage scans was recently completed using 176 multiplex PCGP families, which has implicated several new genomic regions for additional study. The strongest evidence for prostate cancer linkage was on chromosome 17 adjacent to the BRCA1 gene. Mutations in the BRCA1 gene have been shown to increase the risk of breast and ovarian cancer in women as well as prostate cancer in men, however BRCA1 mutations have not been previously identified in prostate cancer families. To further characterize the role of BRCA1 in hereditary prostate cancer and to define other prostate cancer susceptibility genes and their associated clinical syndromes, the following three Specific Aims are proposed: 1) To evaluate the role of the breast cancer gene BRCA1 as a prostate cancer susceptibility gene in PCGP families, 2) to localize and characterize candidate prostate cancer susceptibility genes in PCGP families, 3) To identify prostate cancer susceptibility genes that specifically influences the risk of developing clinically aggressive prostate cancer. Completion of these aims will improve our understanding of the genes that predispose men to prostate cancer as well as the clinical syndromes associated with specific gene mutations. Ultimately, this information may have clinical utility to identify those men at highest risk of prostate cancer who may benefit from early detection and/or chemoprevention strategies.