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: 10447766
• 负责人: David C Christiani
• 金额: $ 60.12万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447766
• 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、医学和内源性产生的dna损伤剂无处不在，然而，在给定的情况下， 暴露只有一小部分人会受到健康影响。本提案主要针对非小细胞肺癌。 癌症(NSCLC)和临床对辐射的敏感性，是一种用于治疗NSCLC的治疗剂。这些代表了 与接触DNA损伤相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志物 可以预测非小细胞肺癌风险或放射治疗副作用严重程度的淋巴细胞。很明显， 个体修复DNA损伤的能力各不相同，DNA修复效率低下是癌症和 其他疾病。然而，到目前为止，使用DNA修复能力的测量来预测 疾病风险或对特定暴露(如辐射)的急性敏感性，因为可用于 测量DNA修复并不能全面评估人类基因组的完整性 人类人口。此外，使用基因组学方法了解个体间差异的努力， 例如转录图谱和全基因组基因分型，留下了关于 已确定的基因组签名的功能分支。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 转录图谱和全基因组基因分型，以全面分析基因组完整性 接受放射治疗的肺癌患者和健康对照组。肺癌患者是关键 疾病通常是由于接触DNA损伤剂而引起的个人群体，并已 与多条途径的DNA修复能力异常有关，每条途径都存在于不同的先前人群中 学习。此外，放射治疗是人体暴露在复杂的dna混合物中的一种定义。 损伤提供了识别可预测个体对DNA敏感性的生物标记物的机会 破坏性因素。我们的研究与以前的工作不同之处在于集成了新的功能分析 利用基因组数据。我们希望找到新的基因组完整性生物标记物来预测辐射剂量。 个体患者可以安全地耐受，以及可能打开个性化癌症大门的生物标记物。 预防和监测战略的基础是确定更有可能患上非小细胞肺癌的个人。 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， 而且由于许多部位的癌症易感性与未能保持基因组的完整性有关， 这项研究的结果可能远远超出非小细胞肺的直接背景而具有普遍性。 癌症。