DNA Repair Phenotype the Missing Link in Breast Cancer Risk Assessment

DNA 修复表型是乳腺癌风险评估中缺失的一环

基本信息

批准号：
10656666
负责人：
DAVID JONATHAN BRENNER
金额：
$ 0.95万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656666
关键词：
Address Age Archives BRCA1 gene BRCA2 gene Biological Assay Biological Markers Biometry Biopsy Blood Blood specimen Breast Cancer Detection Breast Cancer Epidemiology Breast Cancer Model Breast Cancer Risk Assessment Tool Breast Cancer Risk Factor Calibration Case-Control Studies Cells Chemoprevention Clinic Clinical DNA DNA Damage DNA Double Strand Break DNA Methylation DNA Repair DNA Repair Gene DNA lesion Defect Development Discrimination Disease Double Effect Double Strand Break Repair Epigenetic Process Freezing Frequencies Genes Genetic Genome Genome Stability Genotype Grant Incidence Individual Investigation Laboratories Lead Link Literature Malignant Neoplasms Mammographic screening Measurement Measures Methodology Methods Modeling Molecular Epidemiology Mutagens Mutation Nested Case-Control Study Nucleotide Excision Repair Oncogenes Outcome Performance Peripheral Blood Lymphocyte Peripheral Blood Mononuclear Cell Phenotype Population Study Predisposition Prevention Primary Prevention Prospective Studies Prospective cohort Proteins Protocols documentation Reporting Research Research Personnel Risk Risk Assessment Risk Factors Role Sample Size Sampling Secondary Prevention System Time Tumor Suppressor Genes Woman adduct base biological specimen archives breast cancer diagnosis breast cancer family registry cancer initiation cancer risk case control clinical application clinical risk cohort design epigenetic marker follow-up gene repair high risk improved individual variation inter-individual variation lymphoblastoid cell line malignant breast neoplasm mortality mutation carrier overtreatment phenotypic biomarker prospective repaired response risk stratification screening young woman

项目摘要

ABSTRACT DNA repair is a crucial mechanism for maintaining genomic stability in cells. Defects in the DNA repair machinery increase cell vulnerability to DNA-damaging agents and accumulation of mutations in the genome, and lead to the development of various disorders including cancers. Studies that have measured DNA repair capacity (DRC), including our own, have estimated a much higher risk of breast cancer (BC) (3-15-fold) than most other established risk factors for BC, with the exception of highly penetrant mutations in genes like BRCA1 and BRCA2, genes critical to DNA repair. Despite the strength of this association, no large-scale prospective studies of BC exist. Even though some BC risk models include known mutations in DNA repair genes, genotype only partially explains phenotype, and BC risk models currently do not include phenotypic DNA repair measures. The lack of inclusion of a major risk factor – DRC – is likely the major reason that clinical BC risk models have only modest performance - which makes it very challenging to target effective primary prevention options (e.g., chemoprevention) for the majority of women who are not known mutation carriers. Further, secondary prevention options (e.g., onset, frequency, and method of BC screening by mammography or other supplemental methods) could be targeted more efficiently if more accurate risk assessment existed. The main limitation of use of DRC for targeted prevention has been the lack of a high-throughput DRC assay, in particular a phenotypic DRC assay, for integration into cancer risk assessment. We have overcome this major gap by adapting our high-throughput, fully-automated ɣ-H2AX assay system which was originally designed for assaying DNA double strand breaks (DSB) in freshly-drawn blood for use with archival blood samples. We propose one of the largest prospective studies estimating the effect of DSB repair using an enriched cohort (n=12,563) that spans the spectrum of absolute BC risk. Using a nested case-control design within this cohort (699 cases, 1:1 match), we will measure DSB-DRC in archival biospecimens collected at baseline (Aim 1a). We will optimize the assay protocol for measuring DSB-DRC using fresh fingerstick blood and measure longitudinal changes in DSB-DRC in young women (age <40 years) (Aim 1b) (n=100, 1-2 years apart). We will then comprehensively assess the independent contribution of DSB-DRC over genetic and epigenetic alterations in DSB repair genes, and assess and whether genetic and epigenetic changes interact with DSB-DRC in increasing BC risk (Aim 2). We will investigate the clinical utility of DSB-DRC by quantifying the improvement in standard BC risk model performance from its inclusion (Aim 3a), and evaluating the association between DSB-DRC and 5 year survival after BC diagnosis (Aim 3b). Our study will provide essential empirical evidence from integrating functional assays into population studies to accelerate targeted prevention options linked to aberrant responses to DNA damage. This research will be led by a team of established investigators in the fields of BC epidemiology, molecular epidemiology, high-throughput DNA repair capacity assessment, and biostatistics.

抽象的 DNA修复是维持细胞基因组稳定性的关键机制。 DNA修复机械中的缺陷增加细胞对DNA伤害剂的脆弱性和基因组突变的积累，并导致包括癌症在内的各种疾病的发展。测量了DNA修复能力的研究（DRC），包括我们自己的包括我们的乳腺癌风险（BC）（3-15倍）比大多数其他 BC已建立的危险因素，除了BRCA1和BRCA2等基因高度渗透突变外对DNA修复至关重要的基因。尽管这种关联的实力，但尚未对卑诗省进行大规模前瞻性研究存在。即使某些BC风险模型包括DNA修复基因中的已知突变，但基因型仅部分地解释表型，BC风险模型当前不包括表型DNA修复措施。缺乏包括主要风险因素 - 刚果民主共和国 - 可能是临床BC风险模型仅适度的主要原因绩效 - 这使得针对有效的初级预防选项非常挑战（例如，化学预防）对于大多数尚不清楚突变携带者的女性。此外，预防选项（例如，通过乳房X线摄影或其他补充方法进行BC筛查的发作，频率和方法）如果存在更准确的风险评估，则可以更有效地针对目标。 DRC使用的主要限制对于有针对性的预防是缺乏高通量DRC分析，特别是表型DRC测定法用于整合到癌症风险评估中。我们通过调整高通量，克服了这一主要差距全自动ɣ-H2AX分析系统最初是为了测定DNA双链断裂的设计（DSB）在新鲜的血液中，与档案血样一起使用。我们提出了最大的准研究使用富集的队列（n = 12,563）估算DSB修复的影响，该研究跨越了范围绝对BC风险。在此队列中使用嵌套的情况对照设计（699个情况，1：1匹配），我们将测量在基线收集的档案生物测量中的DSB-DRC（AIM 1A）。我们将优化针对的测定协议使用新鲜的指尖血和DSB-DRC的测量纵向变化来测量DSB-DRC 妇女（年龄<40岁）（AIM 1B）（n = 100，1-2岁）。然后，我们将全面评估 DSB-DRC对DSB修复基因的遗传和表观遗传学改变的独立贡献以及评估以及遗传和表观遗传学变化是否在增加BC风险的情况下与DSB-DRC相互作用（AIM 2）。我们将通过量化标准BC风险模型性能的改善来研究DSB-DRC的临床实用性从包含（AIM 3A）中，评估DSB-DRC和BC后5年生存之间的关联诊断（AIM 3B）。我们的研究将提供基本的经验证据，从将功能分析整合到人口研究加速了针对针对DNA损伤异常反应的靶向预防选择。这研究将由卑诗省流行病学领域的成熟研究人员团队领导流行病学，高通量DNA维修能力评估和生物统计学。