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Principal Investigator: Silvia Balbo
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $559,809
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <21+ years old><Absolute ethanol><Acetaldehyde><Adult><Adult Human><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcoholic beverage heavy drinker><Alcohols><Aldehydes><Biological Markers><Blood><Blood Reticuloendothelial System><Buccal Cavity><Buccal Cavity Head and Neck><COVID-19 affected><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><Cancer Causing Agents><Cancers><Carcinogen-DNA Adducts><Carcinogens><Cavitas Oris><Cell Body><Cell Line><CellLine><Cells><Chemicals><Chronic><Common Rat Strains><Congenital Pancytopenia><Consumption><DNA><DNA Adducts><DNA Alteration><DNA Damage><DNA Injury><DNA Modification><DNA Modification Process><DNA Sequence Alteration><DNA mutation><Data Analyses><Data Analysis><Deoxyribonucleic Acid><Development><Dose><Drug Metabolic Detoxication><Drug Metabolic Detoxification><ETOH><Early Diagnosis><Enzyme Gene><Enzymes><Epidemiology><Esophagus><EtOH drinking><EtOH use><Ethanal><Ethanol><Ethanol Metabolism><Ethyl Alcohol><Exposure to><Face><Fanconi Anemia><Fanconi Panmyelopathy><Fanconi dysplasia><Fanconi's Anemia><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genetics-Mutagenesis><Goals><Grain Alcohol><Head and Neck Cancer><Head and Neck Carcinoma><Health><Heavy Drinker><Heterozygote><Homozygote><Human><Impairment><Individual><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Intermediary Metabolism><Knowledge><LC/MS><Lip and Oral Cavity Neoplasm><Lip and Oral Cavity Tumour><Liver><Malignant Head and Neck Neoplasm><Malignant Neoplasms><Malignant Oral Cavity Neoplasm><Malignant Oral Cavity Tumor><Malignant Oral Neoplasm><Malignant Tumor><Measurement><Measures><Metabolic><Metabolic Drug Detoxications><Metabolic Processes><Metabolism><Metabolism of Toxic Agents><Methods><Methylcarbinol><Modeling><Modern Man><Modification><Mouth><Mouth Cancer><Mouth Neoplasms><Mouth Tumor><Mouth microbiome><Mucosa><Mucosal Tissue><Mucous Membrane><Mutagenesis><Mutagenesis Molecular Biology><Mutation><Oncogens><Oral><Oral Cancer><Oral Cavity Neoplasm><Oral Cavity Tumor><Oral Neoplasms><Oral Tumor><Oral cavity><Participant><Patient Recruitments><Patients><Play><Predisposition><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Primary Erythroid Hypoplasia><Process><Rat><Rats Mammals><Rattus><Reaction><Reporting><Risk><Risk Factors><Role><Sales><Saliva><Sampling><Sequence Alteration><Site><Solid><Stomach><Strains Cell Lines><Susceptibility><Techniques><Testing><Time><Translating><Tumor Tissue><Work><adduct><adulthood><alcohol exposed><alcohol exposure><alcohol ingestion><alcohol intake><alcohol metabolism><alcohol product use><alcohol use><alcoholic beverage consumption><alcoholic drink intake><bio-markers><biologic marker><biomarker><cancer location><cancer risk><cancer site><carcinogenicity><congenital aplastic anemia><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease-19 impact><cultured cell line><data interpretation><data mining><datamining><detoxification><developmental><drinking><early detection><epidemiologic><epidemiological><ethanol consumption><ethanol drinking><ethanol exposed><ethanol exposure><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><faces><facial><gastric><genome mutation><genome scale><genome-wide><genomewide><genomic alteration><genotoxicity><head/neck cancer><healthy volunteer><hepatic body system><hepatic organ system><heterozygosity><high risk><liquid chromatography mass spectrometry><malignancy><malignant head and neck tumor><malignant mouth neoplasm><malignant mouth tumor><microbiome><microbiome community composition><microbiome composition><microbiome species composition><microbiome structure><multiomics><multiple omics><neoplasm/cancer><oncogenic agent><oral carcinogenesis><oral cavity cancer><oral microbial community><oral microbiome><oral microbiota><oral microflora><oral neoplasia><panomics><participant recruitment><repair><repaired><social role><tool><trend>