Dissecting the role of acetaldehyde in oral carcinogenesis

剖析乙醛在口腔癌发生中的作用

• 批准号: 10345780
• 负责人: Silvia Balbo
• 金额: $ 48.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345780
• 关键词: Acetaldehyde; Address; Adult; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Aldehydes; Biological Markers; Blood; COVID-19 impact; Carcinogens; Cell Line; Cells; Chemicals; Chronic; Consumption; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Modification Process; DNA Sequence Alteration; Data Analyses; Development; Dose; Drug Metabolic Detoxication; Early Diagnosis; Enzymes; Epidemiology; Esophagus; Ethanol; Ethanol Metabolism; Exposure to; Face; Fanconi' s Anemia; Genetic; Goals; Head and Neck Cancer; Health; Heterozygote; Homozygote; Human; Impairment; Individual; Induced Mutation; Knowledge; Lead; Liver; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolism; Methods; Modeling; Modification; Mouth Neoplasms; Mucous Membrane; Mutagenesis; Mutation; Oral; Oral Characters; Oral cavity; Participant; Patient Recruitments; Patients; Play; Predisposition; Prevention; Prevention strategy; Process; Rattus; Reaction; Reporting; Risk; Risk Factors; Role; Sales; Saliva; Sampling; Site; Solid; Stomach; Techniques; Testing; Time; Translating; Tumor Tissue; Work; adduct; alcohol exposure; base; cancer risk; cancer site; carcinogenicity; data mining; drinking; genome-wide; genotoxicity; healthy volunteer; high risk; liquid chromatography mass spectrometry; malignant mouth neoplasm; microbiome; microbiome composition; multiple omics; oral carcinogenesis; oral microbial community; oral microbiome; repaired; tool; trend

Ethyl alcohol (henceforth ethanol) is a human carcinogen.1,2 Its consumption has been associated with cancers at various sites, including the oral cavity. Despite strong epidemiological evidence, the mechanisms of ethanol carcinogenicity remain unclear, hampering the ability to develop efficacious preventive strategies, identify individual susceptibility, and effectively face the challenges deriving from the projected increase in consumption. Ethanol major metabolite, acetaldehyde (AA), is suggested to play a crucial role in head and neck cancers by reacting with DNA. These reactions generate chemical modifications (DNA adducts) that, if not repaired, may result in mutations and ultimately lead to cancer. Individuals with genetic deficiencies in ALDH2, the enzyme responsible for AA detoxification, were shown to have a 15% increased risk of developing oral cancer when drinking.5 Additionally, Fanconi Anemia (FA) patients, who have impaired mechanisms to repair AA-related DNA damage, have an average 500-fold higher chance of developing oral cancer.6 Previous studies have shown a direct and dose-dependent connection between ethanol consumed and AA-derived DNA damage, in the oral cavity of healthy volunteers.7 This effect was not as evident in blood DNA from the same individuals, indicating a distinct contribution of AA exposure coming from oral ethanol metabolism by the mucosa and oral microbiome. Our hypothesis is that AA resulting from oral metabolism of ethanol is playing a crucial role in oral cancer through the formation of DNA adducts, and that levels and persistence of driver adducts will increase in individuals with increasing oral cancer risk. Using cutting-edge analytical approaches, our objective is to characterize ethanol's oral metabolism and its corresponding DNA damage and mutational profiles, to develop a systematic assembly of biomarkers for identifying oral cancer risk and for developing strategies for early detection and prevention. This will be done by completing 3 aims. The first one will characterize DNA damage profiles in oral cells, collected after exposure to a controlled alcohol dose from participants from 3 groups at increasing risk of AA-related oral cancer (active ALDH2*1/1* homozygotes, inactive ALDH2*1/2* heterozygotes and FA patients). Driver adducts will be identified as those increasing in the groups following the increased cancer risk and persisting over time in FA patients. The second aim will focus on investigating the role of the oral microbiome in ethanol metabolism, by characterizing the oral microflora and measuring the aldehyde profile resulting from the ethanol dose in the saliva of study participants. Additionally, the oral microbiome will be characterized in samples from non-drinkers, included to investigate if ethanol consumption results in a specific profile. Finally, the third aim will analyze genome-scale mutational signatures in oral cell lines exposed to AA, for which DNA adducts will be profiled, and in oral tumor tissues from rats chronically exposed to AA or ethanol. This will yield mechanistic evidence on ethanol-related oral mutagenesis and cancer formation and identify DNA adducts bearing mutagenic potential.

乙醇（以下简称乙醇）是一种人类致癌物。1,2 其消费与癌症有关 在不同的部位，包括口腔。尽管有强有力的流行病学证据，乙醇的机制 致癌性仍不清楚，阻碍了制定有效预防策略、识别致癌性的能力 个人的敏感性，并有效应对预期消费增长带来的挑战。 乙醇主要代谢物乙醛（AA）被认为在头颈癌中发挥着至关重要的作用 与DNA发生反应。这些反应会产生化学修饰（DNA 加合物），如果不加以修复，可能会 导致突变并最终导致癌症。具有 ALDH2（酶）遗传缺陷的个体 负责 AA 解毒的物质，被证明在以下情况下患口腔癌的风险增加 15% 5 此外，范可尼贫血 (FA) 患者的 AA 相关 DNA 修复机制受损 损伤，患口腔癌的几率平均高出 500 倍。6 先前的研究表明， 口服乙醇与 AA 衍生的 DNA 损伤之间存在直接且剂量依赖性的联系 7 这种效应在同一个体的血液 DNA 中并不明显，表明 AA 暴露的一个明显贡献来自粘膜和口腔微生物组的口腔乙醇代谢。 我们的假设是，乙醇口腔代谢产生的 AA 在口腔癌中发挥着至关重要的作用 通过 DNA 加合物的形成，驱动加合物的水平和持久性将增加 口腔癌风险增加的个体。使用尖端的分析方法，我们的目标是 表征乙醇的口服代谢及其相应的 DNA 损伤和突变谱，以开发 用于识别口腔癌风险并制定早期策略的生物标志物的系统组合 检测和预防。这将通过完成 3 个目标来完成。第一个将描述 DNA 损伤的特征 口腔细胞的概况，是在暴露于受控酒精剂量后收集的，来自 3 组的参与者 增加 AA 相关口腔癌的风险（活性 ALDH2*1/1* 纯合子、非活性 ALDH2*1/2* 杂合子 和 FA 患者）。驱动加合物将被确定为在增加后组中增加的那些 FA 患者的癌症风险及其随时间的推移而持续存在。第二个目标将侧重于调查口头的作用 通过表征口腔微生物群和测量醛谱来研究乙醇代谢中的微生物组 由研究参与者唾液中的乙醇剂量引起。此外，口腔微生物组将 对来自非饮酒者的样本进行特征分析，包括调查乙醇消耗是否会导致特定的结果 轮廓。最后，第三个目标将分析暴露于 AA 的口腔细胞系的基因组规模突变特征， 将分析哪些 DNA 加合物，以及长期暴露于 AA 或乙醇的大鼠口腔肿瘤组织中的情况。 这将产生乙醇相关口腔诱变和癌症形成的机制证据，并鉴定 DNA 具有致突变潜力的加合物。