Breast Cancer Risk Enhancers

描述(由申请人提供)：乳腺癌风险增强乳腺癌(BCA)遗传风险部分由罕见的病理突变(例如BRCA1和BRCA2)和导致风险的&gt；70常见变异所解释；后者由全基因组关联(GWAS)点击揭示。Gwas基因座的主要“问题”是缺乏对这些风险等位基因如何发挥作用以及它们如何导致遗传风险的机械性理解。绝大多数(90%的BCA风险等位基因)存在于非编码DNA中，如增强子，这一事实进一步加剧了这一情况。本申请旨在系统地阐明20个新发现的BCA风险增强剂的作用机制和靶基因。这将通过测量等位基因特异性增强子活性(目标1)、等位基因特异性核小体消耗和转录因子占有率(目标2)、使用eQTL、3C和CRIPR/CA确定风险增强子靶基因(目标3)以及最后根据癌症表型确定风险基因的功能(目标4)来实现。这一结果将把变异的功能与乳房生物学联系起来，并阐明以前未曾预料到的风险机制。这些结果将对疾病的许多方面产生重大影响，包括基于人群的筛查以早期发现疾病，以及新的治疗方法。

DESCRIPTION (provided by applicant): Breast Cancer Risk Enhancers Breast cancer (BCa) genetic risk is partly explained by rare pathological mutations (BRCA1 and BRCA2, for example) and >70 common variants that contribute to risk; the latter as revealed by genome-wide association (GWAS) hits. The major 'problem' of GWAS loci is the lack of mechanistic understanding of how such risk alleles function and how they contribute to genetic risk. This is further exacerbated by the fact that the vast majority (>90% of BCa risk alleles) resides in non-coding DNA such as enhancers. This application intends to systematically elucidate mechanisms of action and target genes of 20 newly identified BCa risk enhancers. This will be achieved by measuring allele-specific enhancer activity (Aim #1), allele-specific nucleosome depletion and transcription factor occupancy (Aim #2), identifying risk enhancer target genes, using eQTL, 3C and CRIPR/Cas (Aim #3) and finally by determining the functionality of risk genes in terms of cancer phenotypes (Aim #4). The results will link functionality of variants with breast biology and elucidate previously unanticipated risk mechanisms. The results will have a major impact on many aspects of disease including population based screening for early disease detection, and new treatments.