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.

项目概要 环境、医学和内源产生的 DNA 损伤剂无处不在，但对于特定的情况 只有一小部分人会受到暴露的健康影响。该提案重点关注非小细胞肺 癌症（NSCLC）和对放射线（用于治疗 NSCLC 的治疗剂）的临床敏感性。这些代表 与暴露 DNA 损伤相关的两个主要健康影响。我们的目标是识别血液中可能的标记物 淋巴细胞可以预测 NSCLC 风险或放射治疗副作用的严重程度。很明显， 每个人修复 DNA 损伤的能力各不相同，低效的 DNA 修复是癌症和癌症的危险因素。 其他疾病。然而，迄今为止，利用 DNA 修复能力的测量来预测尚不可行。 疾病风险或对特定暴露（例如辐射）的急性敏感性，因为可用于 测量 DNA 修复尚不适合对基因组完整性进行全面评估 人口。此外，利用基因组学方法来理解个体差异的努力， 例如转录谱分析和全基因组基因分型，留下了有关 已识别的基因组特征的功能后果。因此，我们将结合尖端技术 对所有主要途径的 DNA 修复能力进行功能评估的技术 转录分析和全基因组基因分型，对基因组完整性进行全面分析 接受放射治疗的肺癌患者和健康对照者。肺癌患者是关键 其疾病通常是由于接触 DNA 损伤剂而引起的人群，并且已被 与多个途径中的异常 DNA 修复能力相关，每个途径都存在于单独的先前群体中 研究。此外，放射治疗是指人体在体内暴露于复杂的 DNA 混合物中。 损伤提供了识别生物标志物的机会，这些生物标志物可以预测个体对 DNA 的敏感性 破坏剂。我们的研究与以前的工作不同之处在于整合了新的功能测定 与基因组数据。我们期望找到可以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 基于识别更有可能罹患 NSCLC 的个体的预防和监测策略。 由于辐射和其他 DNA 损伤剂是多种癌症治疗的关键组成部分， 而且由于许多部位的癌症易感性与未能维持基因组完整性有关， 这项研究的结果可能会远远超出非小细胞肺的直接背景 癌症。