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妇女的乳腺癌中起着重要作用。由于非洲裔个体的遗传异质性较高，常见病-常见病等位基因遗传因果模型不适用于非洲裔女性的乳腺癌。因此，到目前为止，基于常见SNP的GWAS和候选基因研究寻找非洲血统乳腺癌患者的风险等位基因，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了解，我们假设非洲裔女性乳腺癌的遗传模型是常见病-许多罕见等位基因模型。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microRNAs），优先考虑罕见的乳腺癌风险等位基因列表。在这些极端表型患者的重要功能外显子组区域中富集的罕见（即在一般人群中频率较低）变异可能作为具有很大效应量的遗传风险等位基因的候选基因。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系。我们的假设是，具有非洲血统的女性携带优先的罕见乳腺癌风险等位基因，患乳腺癌的风险增加。因为这项研究是嵌套在妇女健康研究圈（WCHS），对象可以在一个及时和成本有效的方式解决。

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. PUBLIC HEALTH RELEVANCE: The results from this study are expected to have an important positive impact, because the identified novel genetic risk alleles are highly likely to provide new clues to the genetic etiology of breast cancer in AA women, shed light on the genetic basis of racial disparity in breast cancer, as well as provide concrete evidence for the novel genetic model: the common disease-many rare alleles model of human diseases.