Genetic Epidemiology of Prostate Cancer

我们从98个包含三个或更多确诊前列腺癌病例的家庭成员中获得了谱系数据、血液和存档组织。我们对这些家族进行了437个常染色体标记的分型，并对数据进行了连锁分析。尽管没有单个染色体区域满足统计学显著过量等位基因共享的全基因组标准，但我们在染色体19 p远端的最强信号已被瑞典多病例前列腺癌家族的研究独立复制（Wiklund et al. 2003）。在这个竞争性的更新申请中，我们要求资金来测试区域19p13.3含有前列腺癌易感基因的假设。我们的目标是：1）通过将标记的数量增加两倍来缩小区域，并进行连锁分析以排除具有低lod分数的亚区域，使用适应个体特异性和家族特异性协变量的统计方法，这些协变量可以解释家族间的遗传异质性; 2a）将92个已知基因和61个未知基因的转录本在基因组中进行排序。2b）鉴定更有希望的基因中的多态性; 3a）通过对750名非洲人进行基因分型，研究前列腺癌风险与所鉴定的多态性中的变异等位基因之间的关联。美国人和750名高加索人病例对照研究嵌套在夏威夷/洛杉矶多种族队列（MEC）; 3b）必要时，调查这些变异的功能意义。由NCI资助的国际前列腺癌遗传学联盟（ICPCG）是1,500多个多病例前列腺癌家族的资源。作为ICPCG的成员，我们的长期目标是与该小组一起寻求该项目中确定的任何有希望的线索。

We have obtained pedigree data, blood and archived tissue from members of 98 families containing three or more confirmed cases of prostate cancer. We have typed these families for 437 autosomal markers and have analyzed the data for linkage. Although no single chromosomal region met the genome-wide criteria for statistically significant excess allele sharing, our strongest signal on the distal end of chromosome 19p has been replicated independently by a study of multiple-case prostate cancer families in Sweden (Wiklund et al. 2003). In this competing renewal application we request funds to test the hypothesis that region 19p13.3 harbors a prostate cancer susceptibility gene. Our objectives are to: 1) narrow the region by tripling the number of markers and perform linkage analysis to exclude subregions with low lod scores, using statistical methods that accommodate both individual-specific and family-specific covariates that may account for genetic heterogeneity across families; 2a) rank the 92 known genes and 61 transcripts of unknown genes in the (narrowed) region with respect to their potential involvement in prostate cancer, and 2b) identify polymorphisms in the more promising genes; 3a) investigate associations between prostate cancer risk and the variant alleles in the identified polymorphisms by genotyping 750 African-American and 750 Caucasian case-control pairs in a casecontrol study nested within the Hawaii/Los Angeles multiethnic cohort (MEC); 3b) when warranted, investigate the functional significance of these variants. The NCI-funded International Consortium for Prostate Cancer Genetics (ICPCG) is a resource of more than 1,500 multiple-case prostate cancer families. As members of the ICPCG, our long-term aim is to pursue with this group any promising leads identified in this project.