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

项目摘要 环境、医学和内源性产生的DNA损伤剂是普遍存在的，然而，对于给定的 只有一部分人的健康受到影响。本提案重点关注非小细胞肺癌 癌症（NSCLC）和对放射的临床敏感性，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物 淋巴细胞可以预测NSCLC的风险，或放射治疗副作用的严重程度。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的危险因素， 其它疾病然而，迄今为止，使用DNA修复能力的测量来预测还不可行 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修复还不适合对基因组完整性进行全面评估， 人类种群。此外，利用基因组学方法理解个体间差异的努力， 例如转录谱分析和全基因组基因分型，留下了关于 所鉴定的基因组签名的功能分支。因此，我们将联合收割机 在所有主要途径中对DNA修复能力进行功能评估的技术， 转录谱分析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。肺癌患者代表了一个关键 其疾病通常由暴露于DNA损伤剂引起的个体群体，并且已经被 与多种途径中异常的DNA修复能力相关，每种途径都在单独的先前人群中 问题研究此外，辐射治疗是指人体在体内暴露于复杂的DNA混合物 损伤提供了一个机会，以确定生物标志物，可以预测个人对DNA的敏感性 破坏剂。我们的研究是区别于以往的工作的整合新的功能测定 with genomic基因data数据.我们希望能发现新的基因组完整性生物标志物，可以预测辐射剂量 个体患者可以安全耐受，以及可能打开个性化癌症之门的生物标志物 基于识别更有可能发展为NSCLC的个体的预防和监测策略。 因为辐射和其他DNA损伤剂是治疗各种癌症的关键组成部分， 并且由于许多位点的癌症易感性与未能保持基因组完整性有关， 这项研究的结果可能是普遍的，远远超出了非小细胞肺的直接背景， 癌

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.