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中聚集，导致许多研究团队，包括我们自己的团队，收集有多个前列腺癌病例的家庭进行连锁研究。不幸的是，尽管收集和分析了大量这样的家系，但导致遗传前列腺癌易感性的主要基因一直难以完全确定。至少有8个基因座已经被提出，现在需要进一步的研究来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。最近完成了对176个多重PCGP家族的全基因组连锁扫描，这意味着需要进一步研究几个新的基因组区域。前列腺癌关联的最有力证据是位于17号染色体上，与BRCA1基因相邻。BRCA1基因突变已被证明会增加女性乳腺癌和卵巢癌以及男性前列腺癌的风险，但此前尚未在前列腺癌家族中发现BRCA1突变。 为了进一步确定BRCA1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的临床症状，提出了以下三个具体目标： 1)评估乳腺癌基因BRCA1作为前列腺癌易感基因在PCGP家系中的作用；2)定位和鉴定PCGP家系中的候选前列腺癌易感基因；3)确定影响临床侵袭性前列腺癌风险的前列腺癌易感基因。完成这些目标将提高我们对易患前列腺癌的基因以及与特定基因突变相关的临床症状的理解。最终，这些信息可能具有临床实用价值，可以识别那些可能从早期发现和/或化学预防策略中受益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.