HEREDITARY PROSTATE CANCER IN AFRICAN AMERICAN FAMILIES

前列腺癌家族史已被证明是最常见的 前列腺癌风险的重要决定因素。使用隔离 分析表明，研究人员已经证明，早发性前列腺癌 在一些家族中，可以用常染色体显性遗传来解释 罕见的易感等位基因。与第一个推测的遗传位点相关的 遗传性前列腺癌易感性，称为HPCL 在染色体1q24-25上，最近通过分析一组 高危前列腺癌家族的成员。分析一组独立的 我们实验室的家属也发现了前列腺癌的证据 与染色体1q标记的连锁。前列腺癌是一种极端的 非洲裔美国男性的重要健康问题，因为年龄调整 非洲裔美国男性前列腺癌的发病率约为 比高加索美国男性高50%。相对风险 与前列腺癌家族史相关的 非洲裔和高加索裔美国男性强调 在两个种族的队列中诱发生殖系突变。非裔美国人 然而，在对遗传基因的研究中，家族的代表性一直不足 易患前列腺癌。此外，对六个非洲国家的分析 我们实验室的美国家庭表明，HPCL可能特别 在这群人中很重要。检验HPCL贡献的假设 对于非裔美国人家庭中前列腺癌的易感性， 提出了以下具体目标：一、识别非裔美国人 有两名或两名以上在世家庭成员患有前列腺癌的家庭 癌症。II.分离DNA并对所有已鉴定的个体进行基因分型 特定目的I使用一组跨越HPCL的多态标记 候选人间隔。使用参数和非参数多点 分析以评估前列腺癌与映射到 1q24-25。收集前列腺癌所有可用的肿瘤样本 患者进行杂合性缺失(LOH)分析，杂合性缺失是 许多肿瘤抑制基因，位于1q24-25。如果HPCL基因被克隆在 这项建议的时间框架，建议进行额外的实验以 鉴定潜在的HPCL突变并检测与其他基因的连锁 前列腺癌家族中潜在的前列腺癌易感基因 不是由于HPCL基因突变引起的癌症。

A family history of prostate cancer has been shown to be one of the most important determinants of prostate cancer risk. Using segregation analysis, investigators have demonstrated that early-onset prostate cancer in some families may be explained by autosomal dominant inheritance of a rare susceptibility allele. The first putative genetic locus associated with the inherited predisposition to prostate cancer, referred to as HPCl at chromosome 1q24-25, was recently identified through analysis of a set of high-risk prostate cancer families. Analysis of an independent set of families in our laboratory has also revealed evidence of prostate cancer linkage to chromosome 1q markers. Prostate cancer is an exceedingly important health problem for African American men, since the age-adjusted incidence of prostate cancer in African American men is approximately fifty percent greater than in Caucasian American men. The relative risk associated with a family history of prostate cancer is similar between African and Caucasian American men emphasizing the importance of predisposing germline mutations in both ethnic cohorts. African American families, however, have been under-represented in studies of the inherited predisposition to prostate cancer. Furthermore, analysis of six African American families in our laboratory suggests that HPCl may be particularly important in this population. To test the hypothesis that HPCl contributes to prostate cancer predisposition in African American families, the following Specific Aims are proposed: I. Identify African American families with two or more living family members affected with prostate cancer. II. Isolate DNA and genotype all individuals identified at Specific Aim I using a panel of polymorphic markers spanning the HPCl candidate interval. III. Use parametric and non-parametric multipoint analysis to assess for linkage of prostate cancer to markers that map to 1q24-25. IV. Collect all available tumor samples from prostate cancer patients for analysis of loss of heterozygosity (LOH), a characteristic of many tumor suppressor genes, at 1q24-25. If the HPCl gene is cloned within the time frame of this proposal, additional experiments are proposed to characterize potential HPCl mutations and to test for linkage to other potential prostate cancer susceptibility loci in families with prostate cancer that is not due to mutations in the HPCl gene.