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）已经确定了与乳腺癌风险相关的14个独立的公共标记等位基因。但是，尚未确定负责这些关联的因果变体，围绕这些标记等位基因的区域尚未彻底筛选影响癌症风险的其他常见或稀有变体。此外，这些标记等位基因中很少有人推广到非洲裔美国妇女。 为了解决这些知识差距，我们建议在1,430例乳腺癌病例中，围绕经过验证的乳腺癌风险标志物的序列区域（包括包含与其他几种癌症相关的多个独立等位基因的大型区域），以及2,289家欧洲护士健康研究和护士健康研究的欧洲祖先控制2,289例乳腺癌控制2和大约500名非洲人的群体和1,000名非洲人控制。所有受试者都有可用的GWAS数据，并且所有受试者均具有有关乳腺癌危险因素的详细前瞻性纵向数据。病例具有有关肿瘤亚型的临床验证信息。 最终的数据将有助于识别每个人群中潜在的常见因果等位基因的集合；评估这些区域是否富含在病例（或对照组）中发现不成比例的稀有变体；并评估这种富集是否因种族，乳腺癌亚型，乳腺癌家族史还是已知的乳腺癌危险因素而变化。 数据还将有助于凭经验评估不同测序设计的效率，包括：根据肿瘤特征对病例进行采样；根据标准风险因素（包括年龄和绝经状态）确定的案例和对照的子集对案件和对照的案例和对照组分别进行采样；以及以高风险和低风险的采样子集取决于收集已知风险SNP的确定。 总之，这个多种族样本包含广泛的遗传多样性，并将为在这些区域中发现稀有变体的出色功能提供出色的能力，而1000个基因组项目可能会遗漏的稀有变体。我们将能够从此测序工作中复制发现，并通过其他当前和计划的乳腺癌协作研究来研究其功能意义，包括乳腺癌和前列腺癌队列联盟和非裔美国人乳腺癌GWAS联盟。 公共卫生相关性：最近发现几个遗传区域与欧洲血统妇女的乳腺癌风险有关，但是这些地区的确切因果变异仍然未知。我们建议在5,000多名欧洲和非裔美国人血统的妇女中全面衡量这些地区的遗传序列。这将有助于将这些关联推广到非洲裔美国妇女，并确定未来功能研究的变体，从而帮助我们更好地了解乳腺癌的生物学。