Breast Cancer Genomics in a Founder Population

描述（由申请人提供）：该项目的目标是通过研究德系犹太人（A J）血统的家庭和患者来确定乳腺癌遗传易感性的其他基因。将对几组人群进行评估：约60个乳腺癌高发的AJ家庭，约900个AJ乳腺癌患者，约100个AJ对照家庭，以及>3000个AJ人群对照。通过对所有已知的遗传性乳腺癌基因进行多次检测，这些家族和患者都是野生型。所提出的实验和分析方法是基于这3个群体独特的历史人口统计学，并结合了家庭内的连锁，跨家庭的单倍型共享，重新测序候选基因，并比较变异等位基因频率在独立确定的情况下与对照。这种方法通过鉴定与这些AJ家族的一个子集中的乳腺癌共分离的CHEK 2的先前未检测到的等位基因来验证，然后证明该等位基因在AJ乳腺癌病例中比在AJ对照中显著更频繁。在功能上，尽管野生型人CHEK 2补充了酵母中Rad53缺失的致死性，但突变等位基因未能做到这一点。大多数家族性乳腺癌仍然无法用BRCA1或BRCA2或其他易感基因的遗传突变来解释。在AJ人群中发现更多的中度转移率的乳腺癌基因对该人群和一般人群的女性都很重要。

DESCRIPTION (provided by applicant): The goal of this project is to identify additional genes for inherited predisposition to breast cancer by studying families and patients of Ashkenazi Jewish (A J) ancestry. Several groups of people will be evaluated: ~60 AJ families with high incidence of breast cancer, ~900 unselected AJ breast cancer patients, ~100 AJ control families, and >3000 AJ population controls. The families and patients are wildtype by multiple tests at all known genes for inherited breast cancer. The proposed experimental and analytic approach is based on the distinctive historical demography of this 3opulation and combines linkage within families, haplotype sharing across families, resequencing candidate genes, and comparison of variant allele frequencies in independently ascertained cases vs. controls. This approach was validated by the identification of a previously undetected allele of CHEK2 co-segregating with breast cancer in a subset of these AJ families, then the demonstration that this allele was significantly more frequent among the AJ breast cancer cases than among AJ controls. Functionally, whereas wildtype human CHEK2 complemented the lethality of a Rad53 deletion in yeast, the mutant allele failed to do so. Most familial breast cancer remains unexplained by inherited mutations in BRCA1 or BRCA2 or other susceptibility genes. Discovery of additional breast cancer genes of moderate penetrance in the AJ population will be important to women both in this population and generally.