Analysis of the predictability of lung cancer using DNA Repair functional assays and cryopreserved blood samples of the PLCO prospective cohort

使用 DNA 修复功能测定和 PLCO 前瞻性队列冷冻保存的血液样本分析肺癌的可预测性

• 批准号: 10641094
• 负责人: ZVI LIVNEH
• 金额: $ 19.11万
• 依托单位: WEIZMANN INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-06 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641094
• 关键词: Adenocarcinoma; Age; Aging; Appearance; Base Excision Repairs; Biological Assay; Biological Markers; Biological Process; Blood; Blood Tests; Blood specimen; Cancer Etiology; Case/Control Studies; Clinical; Cryopreservation; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; Data; Diagnosis; Diagnostic; Disease; Early Diagnosis; Effectiveness; Enzymes; Etiology; Freezing; Goals; Histology; Individual; Inherited; Knowledge; Lung nodule; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metabolism; Methods; Modeling; Mutation; Nested Case-Control Study; Non-Small-Cell Lung Carcinoma; OGG1 gene; Occupational; Outcome Study; Pathway interactions; Play; Prevention; Prospective cohort; Prospective, cohort study; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Radiation; Reporting; Reproducibility; Research; Risk; Risk Assessment; Risk Estimate; Risk Factors; Role; Sampling; Selection Criteria; Smoker; Smoking; Smoking Status; Squamous cell carcinoma; T-Lymphocyte; Testing; Time; Tobacco smoke; Whole Blood; biomarker validation; cancer risk; cancer type; carcinogenesis; carcinogenicity; case control; design; enzyme activity; epidemiology study; improved; low dose computed tomography; lung cancer screening; lung development; never smoker; oxidative DNA damage; prevent; repair enzyme; repaired; risk prediction; screening; tumor

Project Summary/Abstract Elucidating the etiology of lung cancer is interwoven with the identification of risk factors for the disease, and is critical to advance prevention, and assist early detection of this lethal tumor. While smoking status and aging are well documented key lung cancer risk factors, along with several additional risk factors including certain environmental and occupational carcinogenic exposures, there is a gap in our knowledge of other important causes of the disease including biological processes that may modify the impact of exposures or be independent risk factors. Because DNA repair ability is key in avoiding mutations and preventing cancer, and likely reflects multiple inherited and other influences, we have previously developed a panel of three functional DNA repair blood tests, which directly measure an individual’s effectiveness at repairing oxidative DNA damage by the enzymes OGG1, MPG and APE1. Using these tests in a case- control study, we found that a low DNA repair score, calculated from the three tests, was strongly associated with lung cancer in addition to and independent of smoking. This was recently replicated in a second case-control study, suggesting that adding the DNA repair score to current lung cancer risk models is likely to substantially improve risk prediction. The data so far is consistent with a causative role in lung cancer, but because the findings are based on case-control studies, where disease bias cannot be ruled out, persuasive evidence to support a role of a low DNA repair score in lung cancer etiology requires demonstrating its ability to predict lung cancer in prospective cohort studies. Our goal is to examine the predictive ability of the DNA repair score for lung cancer in a nested case- control study within a prospective cohort, namely the PLCO Screening Trial. DNA repair activity will be measured in expanded T cells from PLCO pre-diagnostic cryopreserved viable whole blood samples of current smokers and never-smokers who subsequently developed lung cancer, and will be compared to samples from matched controls who did not develop any type of cancer, from which the ability to predict lung cancer can be inferred. Further, DNA repair tests will be expanded with three new functional tests for the DNA repair enzymes TDG, SMUG1 and NEIL1. Using a set of test samples received from the PLCO Trial, we have demonstrated that T cells could be effectively and efficiently expanded from whole blood samples cryopreserved for 12 or 20 years, and were suitable for measuring all six DNA repair enzyme activities, yielding reproducible values comparable to fresh lymphocytes. A successful outcome of this study will support the role of sub-optimal DNA repair of oxidative DNA damage in the etiology of lung cancer, and will facilitate the adaptation of the DNA repair score into clinically-validated biomarkers for risk assessment of lung cancer. This is expected to improve risk estimates, and provide better selection criteria for early detection of lung cancer by methods such as low-dose CT. 1

项目概要/摘要 阐明肺癌的病因与确定该疾病的危险因素交织在一起， 对于促进预防并帮助在吸烟状态下早期发现这种致命肿瘤至关重要。 和衰老是肺癌的关键危险因素，还有其他一些危险因素 包括某些环境和职业致癌暴露，我们的知识存在差距 该疾病的其他重要原因，包括可能改变影响的生物过程 因为 DNA 修复能力是避免突变的关键。 预防癌症，并可能反映多重遗传和其他影响，我们之前已经开发出 一组三项功能性 DNA 修复血液测试，直接测量个人的有效性 通过 OGG1、M​​PG 和 APE1 酶修复氧化 DNA 损伤 在案例中使用这些测试。 对照研究中，我们发现根据三项测试计算得出的低 DNA 修复分数对 这与吸烟无关且与肺癌有关，最近在一项研究中得到了证实。 第二项病例对照研究，表明将 DNA 修复评分添加到当前的肺癌风险模型中 可能会大大改善风险预测，到目前为止的数据与肺部的致病作用一致。 癌症，但因为这些发现是基于病例对照研究，不能排除疾病偏倚 需要有说服力的证据来支持低 DNA 修复评分在肺癌病因学中的作用 在前瞻性队列研究中证明了其预测肺癌的能力。 我们的目标是检查嵌套病例中 DNA 修复评分对肺癌的预测能力 - 前瞻性队列中的对照研究，即 PLCO 筛选试验将进行 DNA 修复活动。 测量了从 PLCO 诊断前冷冻保存的活全血样本中扩增的 T 细胞 当前吸烟者和后来患上肺癌的从不吸烟者，并将与 来自未患任何类型癌症的匹配对照的样本，从中预测的能力 此外，还可以推断，DNA 修复测试将通过三种新的功能测试进行扩展。 DNA 修复酶 TDG、SMUG1 和 NEIL1 使用从 PLCO 收到的一组测试样本。 试验证明，T细胞可以有效且高效地从全血中扩增 样品冷冻保存 12 或 20 年，适合测量所有六种 DNA 修复酶 活性，产生可与新鲜淋巴细胞相媲美的可重复值。 研究将支持氧化性 DNA 损伤的次优 DNA 修复在肺病因学中的作用 癌症，并将促进 DNA 修复评分适应临床验证的风险生物标志物 预计这将改善肺癌的风险评估，并提供更好的选择标准。 通过低剂量CT等方法早期发现肺癌。 1