Repair of tobacco carcinogens in the susceptibility of lung cancer

描述（由申请人提供）：吸烟是美国癌症死亡的单一主要原因，也是许多癌症的危险因素，包括肺癌、上气消化道、膀胱癌和胰腺癌。目前旨在控制肺癌的策略在很大程度上仍然不成功。早期发现仍然是提高生存率的关键。通过将筛查重点放在最易患烟草诱发肺癌的少数吸烟者身上，确定患烟草诱发癌症风险增加的个体将有助于公共卫生。DNA修复效率低下是增加个体罹患烟草诱发肺癌风险的一个特征。目前的范例是使用特定致癌物和通用DNA修复测试来评估DNA修复能力。问题是，烟草含有多种致癌物，这些致癌物会产生多种DNA损伤，并具有一系列突变性，可通过多种机制进行修复。该项目的长期目标是开发高度特异性的DNA修复测试，可以同时测量多种DNA加合物的修复能力。目前的目标是开发和验证一种HPLC-MS/MS分析方法，该方法可以测量由两种最有效的烟草烟雾致癌物苯并[a]芘和4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮形成的单个到十个DNA加合物的修复能力。我们将检验的假设是腺细胞癌或鳞状细胞癌的风险取决于特定DNA加合物的修复，而不是其他。这一假设将在两个方面得到检验。首先，将开发并验证一种可以测量十种DNA加合物的高特异性HPLC-MS/MS分析方法。其次，该假设将在以医院为基础的病例对照研究中得到检验。这个项目可以改变DNA修复测定的模式，在这种模式中，选择用于修复的加合物将基于对癌症病因的理解。

DESCRIPTION (provided by applicant): Tobacco-smoking is the single major cause of cancer mortality in the US, and is a risk factor for a number of cancers including lung, upper aero-digestive tract, bladder and pancreas. Current strategies aimed at the control of lung cancer remain largely unsuccessful. Early detection remains the key to increased survival. Identification of individuals who are at increased risk to tobacco-induced cancers would aid public health by focusing the screening to a limited set of smokers who are most susceptible to tobacco-induced lung cancer. Inefficient DNA repair is a characteristic that increases the risk for an individual to get tobacco-induced lung cancer. The current paradigm is to evaluate DNA repair capacities using specific carcinogens with a generalized DNA repair test. The problem is that tobacco contains multiple carcinogens that produce a variety of DNA damage with a range of mutagenicities that are repaired by multiple mechanisms. The long-term goal of this project is to develop highly specific DNA repair tests that can measure the repair capacity of multiple DNA adducts simultaneously. The current goal is to develop and validate an HPLC-MS/MS assay that can measure the repair capacity of individual to ten DNA adducts that form from two of the most potent tobacco smoke carcinogens, benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. The hypothesis that we will test is that the risk of adeno- or squamous cell carcinoma is dependent of the repair of specific DNA adducts but not others. This hypothesis will be tested in two aims. First, a highly specific HPLC-MS/MS assay that can measure ten DNA adducts will be developed and validated. Second, the hypothesis will be tested in a hospital-based case-control study. This project can change the paradigm by which DNA repair assays are conducted in which the adduct chosen to be analyzed for repair will be based upon an understanding of the etiology of the cancer.