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: 10693217
• 负责人: STEPHEN S HECHT
• 金额: $ 62.86万
• 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/10693217
• 关键词: Acrolein; Adult; Affect; Alcohol consumption; Alcoholic Beverages; Alcoholic beverage heavy drinker; Alcohols; Cancer Etiology; Carcinogens; Cells; Characteristics; Cigarette Smoker; Collecting Cell; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Structure; DNA analysis; Data; Disease; Early Diagnosis; Electrospray Ionization; Genes; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Heavy Drinking; Human; Human Papillomavirus; Incidence; Individual; Intervention; Larynx; Life Style; Light; Lipid Peroxidation; Malignant Neoplasms; Measurement; Methodology; Methods; Monitor; Mucous Membrane; Mutation; Names; Operative Surgical Procedures; Oral; Oral Examination; Oral cavity; Patients; Pattern; Persons; Pharyngeal structure; Predisposition; Prevention; Process; Research; Resolution; Risk; Sampling; Smoker; Smoking; Source; Surface; Testing; Time; Tissues; Tobacco; adduct; analytical method; carcinogenicity; cigarette smoke; cigarette smoking; comparison group; high risk; indexing; nano-liquid chromatography; 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.

头部和颈部的方形细胞癌（HNSCC）是一种毁灭性的，经常毁容，并且经常 致命疾病预计在2020年在美国影响53,000多人，并杀死10,000多人。 预防这种可怕的疾病至关重要。吸烟，饮酒和人乳头瘤 病毒（HPV）是HNSCC的主要原因；只有吸烟和饮酒是 在这里考虑。吸烟和酒精饮料是多种DNA加合物的来源 在致癌过程中。该建议将建立液相色谱 - 纳米电喷雾电离 - 高分辨率串联质谱（LC-NSI-HRMS/MS）的剖面分析分析12个口腔DNA加合物 可能是HNSCC的原因。这是我们最近对口腔细胞中DNA加合物的分析的启发 我们发现，吸烟者的水平比非吸烟者高20倍以上。这些令人兴奋 结果鼓励我们提出对口腔细胞中重要致癌DNA加合物的概况分析 根据以下特定目的： 1。开发一种LC-NSI-HRMS/MS配置文件分析方法，用于定量12个重要和代表性 致癌物和毒物 - 人口腔细胞和组织中的DNA加合物。加合物是从 香烟烟雾和酒精卧室中的各种致癌物和DNA反应性化合物。 2.将目前健康个体的口腔细胞分析分析：a）100名非吸烟者非吸烟者 饮酒者或轻度饮酒者； b）100名非饮用者或饮酒者的吸烟者；和c）100 吸烟者是现代饮酒者。 A和B组中加合物水平的比较 将通过吸烟增强的加合物，而B组的比较将确定 吸烟与中等或大量饮酒的组合增强的加合物。 3。测试50个月内口服细胞DNA添加剂分析分析的纵向稳定性 非饮酒者或轻饮者的吸烟者。 4。 在200名没有HNSCC的吸烟者中，在特定目标2中招募了该吸烟者，目的是识别加合物配置文件 这是HNSCC事件的特征。 b）将此目的A部分A的口腔细胞DNA加合物曲线比较在正常和正常的组织中 肿瘤，在A部分接受手术的60例患者的子集中，以确定口腔细胞DNA是否 加合物模式与组织中的模式一致。 我们的结果可能会确定容易受到HNSCC但无法戒烟的人。 一旦确定，在这些主题（例如口腔检查）中进行了积极的生活方式和监测干预措施 每年可以启动2-4次，以预防或早期发现这种毁容和致命的癌症。

项目成果

Quantitation by Liquid Chromatography-Nanoelectrospray Ionization-High-Resolution Tandem Mass Spectrometry of Multiple DNA Adducts Related to Cigarette Smoking in Oral Cells in the Shanghai Cohort Study.

• DOI: 10.1021/acs.chemrestox.2c00393
• 发表时间: 2023-02-20
• 期刊: CHEMICAL RESEARCH IN TOXICOLOGY
• 影响因子: 4.1
• 作者: Cheng, Guang;Guo, Jiehong;Wang, Renwei;Yuan, Jian-Min;Balbo, Silvia;Hecht, Stephen S.
• 通讯作者: Hecht, Stephen S.