Breast Cancer Risk Enhancers

乳腺癌风险增强剂

• 批准号: 8791816
• 负责人: Gerhard A Coetzee
• 金额: $ 37.7万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791816
• 关键词: Affect; Alleles; BRCA1 Mutation; BRCA2 gene; Binding; Biological Assay; Biology; Breast; Breast Cancer Genetics; Cancer Biology; Candidate Disease Gene; Cell Line; Clinical; DNA; Data; Detection; Diabetes Mellitus; Disease; Enhancers; Exons; Gene Targeting; Genes; Genetic Risk; Genetic Variation; Genetic study; Genomics; Health; Heart Diseases; In Vitro; Individual; Intervention; Link; MCF10A cells; MCF7 cell; Malignant Neoplasms; Measures; Modeling; Nucleosomes; POU2F1 gene; Persons; Phenotype; Population; Predisposition; Response Elements; Risk; SP1 gene; Single Nucleotide Polymorphism; TAL1 gene; Untranslated RNA; Variant; Work; cancer risk; follow-up; genetic variant; genome wide association study; indexing; knock-down; malignant breast neoplasm; population based; promoter; risk variant; screening; trait; transcription factor

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.

乳腺癌（BCa）遗传风险部分由罕见的病理性突变（例如BRCA 1和BRCA 2）和>70种导致风险的常见变异解释;后者由全基因组关联（GWAS）命中揭示。GWAS基因座的主要“问题”是缺乏对这些风险等位基因如何起作用以及它们如何促成遗传风险的机制性理解。这进一步加剧了绝大多数（>90%的BCa风险等位基因）存在于非编码DNA如增强子中的事实。本申请旨在系统地阐明20种新发现的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（Aim#1）、等位基因特异性核小体消耗和转录因子占用（Aim#2）、使用eQTL、3C和CRIPR/Cas鉴定风险增强子靶基因（Aim#3）以及最后通过确定风险基因在癌症表型方面的功能性（Aim#4）来实现。研究结果将把变体的功能与乳腺生物学联系起来，并阐明以前未预料到的风险机制。这些结果将对疾病的许多方面产生重大影响，包括基于人群的早期疾病检测筛查和新的治疗方法。