Sequencing regions assoc with breast cancer risk in European and African American

欧洲和非裔美国人中与乳腺癌风险相关的区域测序

• 批准号: 8005883
• 负责人: PETER KRAFT
• 金额: $ 25.78万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005883
• 关键词: 8q24; Address; Affect; African American; Age; Alleles; Biology; Breast; Breast Cancer Risk Factor; Cancer Control; Characteristics; Chromosomes; Collection; Data; Ethnic Origin; European; Family history of; Future; Genetic; Genetic Variation; Genome; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Menopausal Status; Nurses' Health Study; Population; Risk; Risk Factors; Risk Marker; Sampling; Tumor Subtype; Variant; Woman; cancer genome; cancer risk; case control; case-based; cohort; design; genome wide association study; malignant breast neoplasm; prospective; public health relevance; tumor

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have identified over 14 independent common marker alleles associated with risk of breast cancer. However, the causal variants responsible for these associations have yet to be identified, and the regions surrounding these marker alleles have not been thoroughly screened for additional common or rare variants that affect cancer risk. Moreover, few of these marker alleles generalize to African American women. To address these knowledge gaps, we propose to sequence regions surrounding validated breast cancer risk markers (including a large region on chromosome 8q24 that contains multiple independent alleles associated with several other cancers) in 1,430 breast cancer cases and 2,289 breast cancer controls of European ancestry from the Nurses Health Study and Nurses Health Study 2 and approximately 500 African American cases and 1,000 African American controls from the Multi-ethnic Cohort. All subjects have GWAS data available, and all have detailed prospective longitudinal data on breast cancer risk factors. Cases have clinically-validated information on tumor subtypes. The resulting data will help identify sets of potential common causal alleles in each population; assess whether these regions are enriched for rare variants that are disproportionately found among cases (or controls); and assess whether this enrichment varies by ethnicity, breast cancer subtype, family history of breast cancer or known risk factors for breast cancer. The data will also help empirically evaluate the efficiency of different sequencing designs, including: sampling a subset of cases based on tumor characteristics; sampling subsets of cases and controls at high and respectively low risk as determined by standard risk factors, including age and menopausal status; and sampling subsets at high and low risk as determined by the collection of known risk SNPs. Together, this multiethnic sample contains a wide spectrum of genetic diversity and will provide excellent power for discovery of rare variants in these regions that may be missed by the 1000 Genomes Project. We will be able to replicate findings from this sequencing effort and investigate their functional significance through other current and planned collaborative studies of breast cancer, including the Breast and Prostate Cancer Cohort Consortium and the African American Breast Cancer GWAS Consortium. PUBLIC HEALTH RELEVANCE: Several genetic regions have recently been found to be associated with risk of breast cancer in women of European ancestry, but the precise causal variant in these regions remains unknown. We propose to comprehensively measure the genetic sequence in those regions in over 5,000 women of European and African American ancestry. This will help will help generalize these associations to African American women, and identify variants for future functional studies, helping us better understand the biology of breast cancer.

描述(由申请人提供)：全基因组关联研究(GWAS)已经确定了14个与乳腺癌风险相关的独立共同标记等位基因。然而，导致这些关联的因果变异尚未确定，这些标记等位基因周围的区域还没有彻底筛选出其他常见或罕见的影响癌症风险的变异。此外，这些标记等位基因中很少有适用于非裔美国女性的。 为了解决这些知识差距，我们建议对护士健康研究和护士健康研究2中的1,430例乳腺癌病例和2,289例欧洲血统的乳腺癌对照病例和多种族队列中的大约500例非洲裔美国人病例和1,000名非洲裔美国人对照的乳腺癌风险标志物周围的区域进行测序(包括染色体8q24上包含与几种其他癌症相关的多个独立等位基因的大区域)。所有受试者都有Gwas数据，并且都有关于乳腺癌危险因素的详细前瞻性纵向数据。这些病例有关于肿瘤亚型的临床验证信息。 由此产生的数据将有助于确定每个人群中潜在的常见因果等位基因集；评估这些区域是否富含在病例(或对照)中发现的不成比例的罕见变异；以及评估这种富集性是否因种族、乳腺癌亚型、乳腺癌家族史或已知的乳腺癌风险因素而异。 这些数据还将有助于经验性地评估不同测序设计的效率，包括：基于肿瘤特征对病例子集进行抽样；对由标准风险因素(包括年龄和绝经状况)确定的高风险和低风险病例和对照的子集进行抽样；以及通过收集已知风险SNPs确定的高风险和低风险子集进行抽样。 总而言之，这个多种族样本包含了广泛的遗传多样性，并将为在这些地区发现1000基因组计划可能遗漏的罕见变异提供极好的动力。我们将能够复制这项测序工作的结果，并通过其他目前和计划中的乳腺癌合作研究来研究它们的功能意义，包括乳腺癌和前列腺癌队列联盟以及非裔美国人乳腺癌GWA联盟。 公共卫生相关性：最近发现几个基因区域与欧洲血统女性患乳腺癌的风险有关，但这些区域的确切原因尚不清楚。我们建议对5000多名欧洲和非洲裔美国人血统的女性进行全面的基因测序。这将有助于将这些关联推广到非裔美国女性，并为未来的功能研究识别变异，帮助我们更好地了解乳腺癌的生物学。