权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10430801
负责人：
DAVID JONATHAN BRENNER
金额：
$ 12.39万
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/10430801
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.

摘要