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

描述（由申请人提供）：有证据表明，遗传易感性在非洲血统女性乳腺癌中起着重要作用。由于非洲血统个体的遗传异质性较高，常见疾病-常见等位基因遗传致病模型不适合非洲血统女性乳腺癌。因此，到目前为止，基于GWAS和候选基因的常见SNP研究在非洲血统的乳腺癌患者中寻找风险等位基因并没有像我们预期的那样成功。显然，迫切需要新的遗传模型和新的方法。随着基因组技术的进步和我们对人类疾病发展中罕见变异的认识，我们推测非洲血统女性乳腺癌的遗传模式是常见病-多罕见等位基因模式。为了验证这一假设，在目前的提案中，我们计划利用尖端的基因组技术，全外显子组测序分析，筛选具有丰富但未解决的乳腺癌遗传易感性的AA个体的整个编码区（包括蛋白质和microRNA），以优先考虑罕见的乳腺癌风险等位基因列表。罕见（即，在这些极端表型患者的功能重要的外显子区域中富集的突变体（其特征在于在一般人群中频率低）可以作为具有相当大的效应大小的遗传风险等位基因的候选者。为了测试它们对乳腺癌风险的贡献，我们将进行病例对照分析，以评估从全外显子组测序中优先选择的罕见变异与乳腺癌风险之间的关联。我们的假设是，非洲血统的女性携带优先罕见的乳腺癌风险等位基因，患乳腺癌的风险增加。由于这项研究是嵌套在妇女的健康研究（WCHS）的圈子，对象可以及时和成本效益的方式来解决。

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.