Breast Cancer Genomics in a Founder Population

创始人群体中的乳腺癌基因组学

• 批准号: 7474677
• 负责人: MARY-CLAIRE KING
• 金额: $ 33.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474677
• 关键词: Alleles; Apoptosis; Ashkenazim; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Bioinformatics; CHEK2 gene; Cancer Patient; Candidate Disease Gene; Cell Cycle Regulation; Complement; Complementary DNA; DNA; DNA Repair; DNA Resequencing; Disease; Evaluation; Family; Family Study; Founder Generation; Frequencies; Gene Family; Gene Frequency; Genes; Genetic Complementation Test; Genetic Heterogeneity; Genetic Predisposition to Disease; Genome; Genotype; Goals; Haplotypes; Hereditary Breast Carcinoma; Heterogeneity; Historical Demography; Human; Incidence; Inherited; Mammary Neoplasms; Mutation; Oncogenes; Pathway interactions; Patients; Penetrance; Population; Population Control; Sampling; Scanning; Series; Site; Susceptibility Gene; Testing; Variant; Woman; Yeasts; base; breast cancer family; cancer genomics; design; follower of religion Jewish; genome-wide analysis; genome-wide linkage; malignant breast neoplasm; mutant; novel; protein expression; protein structure; steroid metabolism; tool

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.

描述(由申请人提供)：这个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，确定更多的乳腺癌遗传易感性基因。将对几组人群进行评估：大约60个AJ乳腺癌高发家庭，大约900名未被选择的AJ乳腺癌患者，大约100个AJ对照家庭，以及&gt；3000个AJ人群对照。通过对所有已知的遗传性乳腺癌基因的检测，这些家庭和患者都是野生型。所提出的实验和分析方法是基于该人群独特的历史人口学特征，并结合了家庭内部的联系、家庭间的单倍型共享、候选基因的重新测序以及在独立确定的病例和对照中变异等位基因频率的比较。通过在这些AJ家系的一个子集中鉴定出以前未检测到的CHEK2与乳腺癌共分离的等位基因，验证了这种方法，然后证明该等位基因在AJ乳腺癌病例中显著高于AJ对照病例。在功能上，虽然野生型人CHEK2补充了酵母中Rad53缺失的致命性，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不能用BRCA1或BRCA2或其他易感基因的遗传突变来解释。在AJ人群中发现更多具有中等外显性的乳腺癌基因将对该人群中的女性和一般女性都很重要。