Multi-Pathway DNA Repair Capacity Measurements in Lung Cancer Patients and Healthy Controls

肺癌患者和健康对照组的多途径 DNA 修复能力测量

• 批准号: 10228767
• 负责人: David C Christiani
• 金额: $ 61.3万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 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/10228767
• 关键词: Acute; Affect; Aftercare; Biological; Biological Assay; Biological Markers; Blood; Blood Cells; Cancer Patient; Case-Control Studies; Cells; Cisplatin; Clinical; Clinical Data; Clinical Investigator; Clinical Sensitivity; Complex Mixtures; DNA Damage; DNA Repair; DNA Repair Pathway; DNA lesion; Data; Data Set; Disease; Dose; Early Diagnosis; Exposure to; Failure; Fluorescence; Foundations; Gamma-H2AX; Gene Expression Profiling; Genetic; Genetic Transcription; Genome; Genomic approach; Genomics; Genotype; Goals; Health; Hospitals; Human; Individual; Individual Differences; Ionizing radiation; Lymphocyte; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Medical; Methodology; Methods; Non-Small-Cell Lung Carcinoma; Participant; Pathway interactions; Patients; Population; Population Study; Predisposition; Prevention Measures; Prevention strategy; Procedures; Radiation; Radiation Dose Unit; Radiation Oncology; Radiation Tolerance; Radiation therapy; Radon; Recovery; Reproducibility; Risk Factors; SNP array; Sampling; Severities; Site; Smoker; Statistical Data Interpretation; Technology; Testing; Therapeutic Agents; Time; Tobacco smoke; Variant; Woman; Work; base; cancer prevention; cancer risk; disorder risk; experience; exposed human population; functional genomics; genetic variant; genome integrity; genome-wide; genomic data; genomic signature; in vivo; individual patient; insight; inter-individual variation; mRNA sequencing; multidisciplinary; novel; personalized cancer therapy; personalized strategies; potential biomarker; repair function; repaired; response; side effect; surveillance strategy; therapeutic DNA; tool; treatment strategy

Project Summary Environmental, medical, and endogenously produced DNA damaging agents are ubiquitous, yet, for a given exposure only a subset of individuals experience health effects. This proposal focuses on non-small cell lung cancer (NSCLC) and clinical sensitivity to radiation, a therapeutic agent used to treat NSCLC. These represent two major health effects associated with exposure DNA damage. Our goal is to identify possible markers in blood lymphocytes that can predict NSCLC risk, or the severity of side effects to radiation therapy. It is clear that individuals vary in their capacity to repair DNA lesions, and inefficient DNA repair is a risk factor for cancer and other diseases. However it has thus far not been feasible to use measurements of DNA repair capacity to predict disease risk or acute sensitivity to a particular exposure (such as radiation), because the methods available for measuring DNA repair have not been amenable to making comprehensive assessments of genomic integrity in human populations. Furthermore, efforts to understand inter-individual differences using genomics approaches, such as transcriptional profiling and genome wide genotyping, leave unanswered questions regarding the functional ramifications of the genomic signatures that are identified. We will therefore combine cutting edge technologies for making functional assessments of DNA repair capacity in all of the major pathways with transcriptional profiling and genome wide genotyping to make a comprehensive analysis of genomic integrity in lung cancer patients undergoing radiation therapy and in healthy controls. Lung cancer patients represent a key population of individuals whose disease is often caused by exposure to DNA damaging agents, and has been associated with aberrant DNA repair capacity in multiple pathways, each in separate, previous population studies. Furthermore, treatment with radiation is a defined in vivo human exposure to a complex mixture of DNA damage that provides an opportunity to identify biomarkers that could predict individual sensitivity to DNA damaging agents. Our study is distinguished from previous work by the integration of new functional assays with genomic data. We expect to identify new genomic integrity biomarkers that may predict the radiation dose an individual patient can safely tolerate, as well as biomarkers that may open the door to personalized cancer prevention and surveillance strategies based on identifying individuals who are more likely to develop NSCLC. Because radiation and other DNA damaging agents are a key component of therapy for a wide variety of cancers, and because cancer susceptibility at many sites has been associated with a failure to maintain genomic integrity, the results of this study are likely to be generalizable well beyond the immediate context of non-small cell lung cancer.

项目摘要 环境，医疗和内生产生的DNA破坏剂无处不在，但对于给定的 暴露只有一部分个人会经历健康影响。该建议重点是非小细胞肺 癌症（NSCLC）和对辐射的临床敏感性，这是一种用于治疗NSCLC的治疗剂。这些代表 与暴露DNA损伤有关的两个主要健康影响。我们的目标是确定血液中可能的标记 可以预测NSCLC风险或副作用对放射治疗的严重程度的淋巴细胞。很明显 个体的修复DNA病变的能力各不相同，而效率低下的DNA修复是癌症和 其他疾病。然而，到目前 疾病风险或对特定暴露的敏感性（例如辐射），因为可用于 测量DNA修复不适合对基因组完整性进行全面评估 人口。此外，使用基因组学方法来理解个体差异的努力， 例如转录分析和基因组广泛的基因分型，留下有关 鉴定的基因组特征的功能分析。因此，我们将结合前沿 在所有主要途径中对DNA维修能力进行功能评估的技术 转录分析和基因组广泛的基因分型，以对基因组完整性进行全面分析 肺癌患者接受放射疗法和健康对照。肺癌患者代表关键 疾病通常是由暴露于DNA损害剂引起的个体的人口，并且已经存在 与多个途径中异常的DNA修复能力相关 研究。此外，辐射的处理是一种定义的体内人类暴露于复杂的DNA混合物 损害提供了一个机会来识别可以预测个人敏感性DNA的生物标志物 有害代理。我们的研究与以前的工作区别在于新功能测定的整合 使用基因组数据。我们期望确定可能预测辐射剂量的新基因组完整性生物标志物 个体患者可以安全耐受，以及可能为个性化癌症打开大门的生物标志物 预防和监视策略基于确定更有可能发展NSCLC的个人。 因为辐射和其他DNA损伤剂是多种癌症治疗的关键组成部分，所以 而且由于许多地点的癌症易感性与无法维持基因组完整性有关 这项研究的结果可能远远超出了非小细胞肺的直接背景 癌症。