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（此后乙醇）是人类致癌物。1,2它的消耗与癌症有关 在包括口腔在内的各种地点。尽管有强烈的流行病学证据，但乙醇的机制 致癌性尚不清楚，阻碍了制定有效预防策略的能力，确定 个体的敏感性，并有效地面对预计消费量增加所带来的挑战。 乙醇主要代谢物乙醛（AA）被建议通过在头颈部和颈部癌症中起关键作用 与DNA反应。这些反应会产生化学修饰（DNA加合物），如果不修复， 导致突变并最终导致癌症。 ALDH2中具有遗传缺陷的个体，酶 负责AA排毒的负责，显示出口腔癌的风险增加15％ 5此外，Fanconi贫血（FA）患者，他们的修复AA相关DNA的机制受损 损坏，平均患口腔癌的机会平均增加500倍。6先前的研究表明 口腔中消耗乙醇和AA衍生的DNA损伤之间的直接和剂量依赖性连接 健康志愿者的空腔。7这种效应在同一个人的血液DNA中并不明显，表明 粘膜和口服微生物组来自口服乙醇代谢的AA暴露的明显贡献。 我们的假设是，由乙醇的口服代谢产生的AA在口腔癌中起着至关重要的作用 通过形成DNA加合物，驱动器加合物的水平和持久性将增加 口腔癌风险增加的人。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损伤和突变特征，以发展 用于识别口腔癌风险和制定早期策略的生物标志物的系统组装 检测和预防。这将通过完成3个目标来完成。第一个将表征DNA损伤 口腔细胞中的特征，暴露于3组的参与者接触后的酒精剂量后收集 增加与AA相关的口腔癌风险（活动ALDH2* 1/1*纯合子，无活性ALDH2* 1/2*杂合子 和FA患者）。驾驶员加合物将被确定为增加的组增加 FA患者的癌症风险和随着时间的流逝持续存在。第二个目标将重点放在调查口头的角色上 乙醇代谢中的微生物组，通过表征口腔微生物并测量醛剖面 由研究参与者的唾液中的乙醇剂量产生。此外，口服微生物组将是 包括来自非饮水机的样品的特征，包括研究乙醇消耗是否导致特定 轮廓。最后，第三个目标将分析暴露于AA的口腔细胞系中的基因组规模突变特征，因为 哪些DNA加合物将被分析，并在长期暴露于AA或乙醇的大鼠的口腔肿瘤组织中。 这将产生有关与乙醇相关的口服诱变和癌症形成的机械证据，并鉴定DNA 具有诱变潜力的加合物。