Sequencing to Identify Novel Breast Cancer Risk Factors in African American Women

测序以确定非裔美国女性新的乳腺癌风险因素

• 批准号: 8279227
• 负责人: Song Liu
• 金额: $ 15.14万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279227
• 关键词: Address; African; African American; Age; Alleles; Breast Cancer Risk Factor; Cancer Patient; Candidate Disease Gene; Case-Control Studies; Clinical Data; Code; Data; Development; Diagnosis; Disease; Epidemiology; Etiology; Exons; Frequencies; General Population; Genetic; Genetic Heterogeneity; Genetic Models; Genetic Predisposition to Disease; Genetic Risk; Genome; Health; Individual; Light; MicroRNAs; Modeling; Outcome; Patients; Phenotype; Play; Proteins; Public Health; Research; Risk; Role; Sequence Analysis; Single Nucleotide Polymorphism; Technology; Testing; Variant; Woman; Women' s Group; Work; base; cancer risk; case control; cost effective; disease characteristic; exome; genetic variant; genome wide association study; human disease; innovation; malignant breast neoplasm; novel; novel strategies; tumor

DESCRIPTION (provided by applicant): Evidence has shown that genetic susceptibility plays a significant role in breast cancer in women with African ancestry. Because of the high levels of genetic heterogeneity in individuals with African ancestry, common disease-common allele genetic causation model does not fit the breast cancer in women with African ancestry. Therefore, common SNP based GWAS and candidate gene studies to search for the risk alleles in breast cancer patients with African ancestry, so far, have not been as successful as we expected. Obviously, new genetic model and new approach are urgently needed. With the advance of genome technology and our understanding of rare variants in the development of human diseases, we hypothesize that genetic model for breast cancer in women with African ancestry is common disease-many rare alleles model. To test this hypothesis, in the current proposal we plan to take advantage of cutting-edge genome technology, whole exome sequencing analysis, to screen the entire coding regions (including both proteins and microRNAs) of selected AA individuals with enriched but unresolved genetic susceptibility of breast cancer, to prioritize a list of rare breast cancer risk allele. Rare (i.e., characterized by low frequency in general population) variants enriched in the functionally important exome regions of these extreme-phenotype patients might serve as candidate of genetic risk alleles with substantially large effect size. To test their contribution to breast cancer risk, we will perform a case control analysis to assess the associations between selected rare variants prioritized from whole exome sequencing and breast cancer risk. Our hypothesis is that women with African ancestry carrying the prioritized rare breast cancer risk alleles are at an increased risk of breast cancer. Because this research is nested within the Women's Circle of Health Study (WCHS), the objects can be addressed in a timely and cost effective manner.

描述（由申请人提供）：证据表明，遗传易感性在非洲血统女性中在乳腺癌中起重要作用。由于非洲血统个体的遗传异质性很高，常见的疾病 - 常见等位基因遗传因果模型不符合非洲血统女性的乳腺癌。因此，到目前为止，基于SNP的GWAS和候选基因研究以寻找非洲血统患者的风险等位基因，尚未像我们预期的那样成功。显然，迫切需要新的遗传模型和新方法。随着基因组技术的发展以及我们对人类疾病发展中稀有变异的理解，我们假设非洲血统女性乳腺癌的遗传模型是常见的疾病 - 罕见等位基因模型。为了检验这一假设，在当前的提案中，我们计划利用尖端的基因组技术，整个外显子组测序分析，以筛选精选的AA个体的整个编码区域（包括蛋白质和microRNA），具有富集但未解决的遗传易感性对乳腺癌的易感性，以优先考虑稀有乳腺癌风险的稀有乳腺癌风险。罕见（即，以一般人群中的低频为特征）变体富含这些极端表型患者功能重要的外显子组区域，可能是遗传风险等位基因的候选，其影响大小较大。为了测试其对乳腺癌风险的贡献，我们将进行案例控制分析，以评估整个外显子组测序和乳腺癌风险优先级的稀有变体之间的关联。我们的假设是，携带优先的稀有乳腺癌风险等位基因的非洲血统的女性患有乳腺癌的风险增加。由于这项研究嵌套在女性卫生研究（WCHS）中，因此可以及时且具有成本效益的方式解决这些物体。