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

• 批准号: 10440447
• 负责人: DAVID JONATHAN BRENNER
• 金额: $ 61.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10440447
• 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

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重要机制。 DNA修复机制的缺陷 增加细胞对 DNA 损伤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 DNA 修复能力 (DRC) 的研究， 包括我们自己在内，估计患乳腺癌 (BC) 的风险比大多数其他国家高得多（3-15 倍） 确定了 BC 的危险因素，但 BRCA1 和 BRCA2 等基因的高渗透性突变除外， 对 DNA 修复至关重要的基因。尽管这种关联很强大，但尚无针对 BC 的大规模前瞻性研究 存在。尽管一些 BC 风险模型包括 DNA 修复基因的已知突变，但基因型仅部分 解释了表型，BC 风险模型目前不包括表型 DNA 修复措施。缺乏 纳入主要风险因素——DRC——可能是临床 BC 风险模型仅具有适度预测的主要原因。 绩效 - 这使得确定有效的一级预防方案非常具有挑战性（例如， 化学预防）适用于大多数未知突变携带者的女性。此外，二级预防 选项（例如，通过乳房 X 线摄影或其他补充方法进行 BC 筛查的开始时间、频率和方法） 如果存在更准确的风险评估，就可以更有效地确定目标。 DRC使用的主要限制 对于有针对性的预防，一直缺乏高通量 DRC 测定，特别是表型 DRC 测定， 纳入癌症风险评估。我们通过调整我们的高通量克服了这一重大差距， 全自动 ɣ-H2AX 检测系统，最初设计用于检测 DNA 双链断裂 (DSB) 存在于新鲜抽取的血液中，用于档案血样。我们提出了最大的前景之一 使用丰富的队列（n = 12,563）评估 DSB 修复效果的研究，该队列涵盖以下范围： 绝对 BC 风险。在该队列中使用嵌套病例对照设计（699 例，1:1 匹配），我们将测量 基线时收集的档案生物样本中的 DSB-DRC（目标 1a）。我们将优化检测方案 使用新鲜指尖血测量 DSB-DRC 并测量年轻人 DSB-DRC 的纵向变化 女性（年龄 <40 岁）（目标 1b）（n=100，间隔 1-2 岁）。然后我们将综合评估 DSB-DRC 对 DSB 修复基因的遗传和表观遗传改变的独立贡献，并评估 以及遗传和表观遗传变化是否与 DSB-DRC 相互作用，增加 BC 风险（目标 2）。我们将 通过量化标准 BC 风险模型性能的改进来研究 DSB-DRC 的临床效用 从其纳入（目标 3a），并评估 DSB-DRC 与 BC 后 5 年生存率之间的关联 诊断（目标 3b）。我们的研究将为将功能分析整合到 人口研究，以加速与 DNA 损伤异常反应相关的有针对性的预防方案。这 研究将由不列颠哥伦比亚省流行病学、分子生物学等领域的资深研究人员领导 流行病学、高通量DNA修复能力评估和生物统计学。