High resolution mass spectrometric profile analysis of carcinogen-DNA adducts in oral cells of cigarette smokers and squamous cell carcinoma of the head and neck

吸烟者口腔细胞和头颈部鳞状细胞癌中致癌物-DNA 加合物的高分辨率质谱分析

• 批准号: 10275874
• 负责人: STEPHEN S HECHT
• 金额: $ 64.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275874
• 关键词: Acrolein; Adult; Affect; Alcohol consumption; Alcoholic Beverages; Alcoholic beverage heavy drinker; Alcohols; Cancer Etiology; Carcinogens; Cells; Characteristics; Cigarette Smoker; DNA; DNA Adducts; DNA Damage; DNA Structure; DNA analysis; Data; Disease; Early Diagnosis; Genes; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Heavy Drinking; Human; Human Papillomavirus; Incidence; Individual; Intervention; Larynx; Life Style; Light; Lipid Peroxidation; Liquid Chromatography; Malignant Neoplasms; Measurement; Methodology; Methods; Monitor; Mucous Membrane; Mutation; Names; Operative Surgical Procedures; Oral; Oral Examination; Oral cavity; Patients; Pattern; Pharyngeal structure; Prevention; Process; Research; Resolution; Risk; Sampling; Smoker; Smoking; Source; Surface; Testing; Time; Tissues; Tobacco; Tobacco use; adduct; analytical method; base; carcinogenicity; cigarette smoke; cigarette smoking; comparison group; high risk; indexing; ionization; nano-electrospray; non-smoker; prevent; problem drinker; recruit; smoking cessation; statistics; tandem mass spectrometry; toxicant; tumor

Squamous cell carcinoma of the head and neck (HNSCC) is a devastating, frequently disfiguring, and often fatal disease, expected to affect more than 53,000 people in the U.S. in 2020 and kill more than 10,000. Prevention of this terrible disease is critical. Cigarette smoking, alcohol consumption, and human papilloma virus (HPV) are well established major causes of HNSCC; only smoking and alcohol consumption are considered here. Cigarette smoking and alcoholic drinks are sources of multiple DNA adducts that are critical in the carcinogenic process. This proposal will establish a liquid chromatography-nanoelectrospray ionization- high resolution tandem mass spectrometry (LC-NSI-HRMS/MS) profile analysis of 12 oral cell DNA adducts that are likely causes of HNSCC. This was inspired by our recent analysis of DNA adducts in oral cells, in which we found levels more than 20 times higher in cigarette smokers than in non-smokers. These exciting results encouraged us to propose a profile analysis of important carcinogen-derived DNA adducts in oral cells according to the following specific aims: 1. Develop an LC-NSI-HRMS/MS profile analysis method for quantitation of 12 important and representative carcinogen and toxicant – DNA adducts in human oral cells and tissue. The adducts are derived from various carcinogens and DNA reactive compounds in cigarette smoke and alcoholic beverages. 2. Apply the profile analysis to oral cells from currently healthy individuals: a) 100 non-smokers who are non- drinkers or light drinkers; b) 100 cigarette smokers who are non-drinkers or light drinkers; and c) 100 cigarette smokers who are moderate or heavy drinkers. Comparisons of adduct levels in groups a and b will identify adducts enhanced by cigarette smoking while comparisons of groups b and c will identify adducts that are enhanced by the combination of smoking and moderate or heavy drinking. 3. Test the longitudinal stability of the oral cell DNA adduct profile analysis over a 6 month period in 50 smokers who are non-drinkers or light drinkers. 4. A) Determine the DNA adduct profile in oral cells collected from 75 smokers with HNSCC and compare to that in 200 smokers without HNSCC recruited in Specific Aim 2 with the goal of identifying an adduct profile that is characteristic of HNSCC incidence. B) Compare the oral cell DNA adduct profile from part A of this aim to that in tissue, both normal and tumor, in a subset of 60 patients from part A who undergo surgery, to determine whether oral cell DNA adduct patterns are consistent with those in tissue. Our results will potentially identify individuals who are susceptible to HNSCC but are unable to quit smoking. Once identified, aggressive lifestyle and monitoring interventions in these subjects such as oral examinations 2-4 times per year can be initiated for prevention or early detection of this disfiguring and often fatal cancer.

头颈鳞状细胞癌 (HNSCC) 是一种破坏性的、经常毁容的癌症 预计到 2020 年将影响美国 53,000 多人，并导致 10,000 多人死亡。 预防这种可怕的疾病至关重要。吸烟、饮酒与人乳头状瘤 病毒 (HPV) 是公认的 HNSCC 的主要原因；仅吸烟和饮酒 这里考虑。吸烟和饮酒是多种至关重要的 DNA 加合物的来源 在致癌过程中。该提案将建立液相色谱-纳电喷雾电离- 对 12 种口腔细胞 DNA 加合物进行高分辨率串联质谱 (LC-NSI-HRMS/MS) 分析 这可能是导致 HNSCC 的原因。这是受到我们最近对口腔细胞中 DNA 加合物的分析的启发， 我们发现吸烟者的胆固醇水平比不吸烟者高 20 倍以上。这些激动人心的 结果鼓励我们提出对口腔细胞中重要的致癌物衍生 DNA 加合物进行概况分析 根据以下具体目标： 1. 开发LC-NSI-HRMS/MS谱分析方法，对12种重要且有代表性的物质进行定量 致癌物和毒物——人类口腔细胞和组织中的 DNA 加合物。加合物源自 香烟烟雾和酒精饮料中的各种致癌物质和 DNA 反应性化合物。 2. 将概况分析应用于当前健康个体的口腔细胞： a) 100 名非吸烟者 饮酒者或轻度饮酒者； b) 100 名不饮酒或少量饮酒的吸烟者； c) 100 适度或大量饮酒的吸烟者。 a、b组加合物水平比较 将确定因吸烟而增强的加合物，而 b 组和 c 组的比较将确定 吸烟和适量或大量饮酒的结合会增强加合物。 3. 在 50 个样本中测试 6 个月内口腔细胞 DNA 加合物谱分析的纵向稳定性 不饮酒或少量饮酒的吸烟者。 4. A) 确定从 75 名患有 HNSCC 的吸烟者收集的口腔细胞中的 DNA 加合物谱，并与 在特定目标 2 中招募了 200 名没有 HNSCC 的吸烟者，目的是确定加合物谱 这是 HNSCC 发病的特征。 B) 将本目标 A 部分的口腔细胞 DNA 加合物谱与正常组织和组织中的口腔细胞 DNA 加合物谱进行比较 在 A 部分接受手术的 60 名患者中，确定口腔细胞 DNA 加合物模式与组织中的一致。 我们的结果将有可能识别出易患 HNSCC 但无法戒烟的个体。 一旦确定，对这些受试者采取积极的生活方式和监测干预措施，例如口腔检查 每年可启动 2-4 次，以预防或及早发现这种毁容且通常致命的癌症。