Effects of ethanol and acetaldehyde on multi-organ genomic mutation landscapes

Alcohol consumption is a major risk factor for cancer, particularly of the head and neck. Acetaldehyde, the main ethanol metabolite, is linked to oral carcinogenesis, but the mechanisms are not well understood. While some mutational signatures such as single-base substitution signature SBS16, doublet-base substitution signature DBS4, and indel signature ID11 have been linked to alcohol use, they are not limited to alcohol-related cancers. We examined the genome-wide in vivo mutation landscapes of rats chronically exposed to ethanol or acetaldehyde, focusing on head-and-neck tumors (involving the cheek and the Zymbal gland) and tumors of the forestomach and liver. Mutational signature analysis revealed early-onset, exposure-associated formation of signature SBS17 in ~ 38% of head-and-neck tumors, suggesting inflammation and oxidative damage may mediate carcinogenesis in these sites. We observed relative enrichment of driver-like mutations in Tp53, Mtor and Hras in exposed tumors, where all Tp53-mutated tumors were SBS17-positive, recapitulating a similar scenario from human gastro-esophageal adenocarcinomas. Next, the doublet-base, indel, copy number and structural variant changes were sporadic and not following exposure-specific patterns. No signatures previously associated with alcohol consumption in humans were observed in the exposed animals. Thus, in this animal cancer model, alcohol-related carcinogenesis across multiple organs is unlikely to be driven mainly by direct mutagenicity of ethanol or acetaldehyde. Rather, the results support a role for non-mutational processes in mediating their carcinogenic effects. Further investigation is warranted to clarify the relationship between mutational signature SBS17 and TP53 loss-of-function mutations as potential biomarkers of alcohol-related carcinogenesis in animals and humans.