# Long-term exposure to the ethanol-derived metabolite acetaldehyde elevates structural genomic alterations but not base substitutions

## TL;DR

Long-term exposure to acetaldehyde, a byproduct of alcohol, causes large DNA changes but not base substitutions, linking it to cancer risk.

## Contribution

Shows acetaldehyde causes structural DNA changes, not base substitutions, and connects these to alcohol-related cancer.

## Key findings

- Acetaldehyde exposure does not increase base substitutions or short insertions/deletions.
- Large genomic deletions and duplications are observed in treated cells and linked to alcohol consumption in gastric cancer.
- DNA breaks and homologous recombination are involved in acetaldehyde-induced genomic alterations.

## Abstract

Acetaldehyde is the primary metabolite of ethanol, and routes of exposure include endogenous sources, food and cigarette smoke. To explore whether the mutagenic effect of acetaldehyde is responsible for the carcinogenicity of ethanol, we use whole genome sequencing on four human cell lines subjected to long-term, physiologically relevant, analytically validated acetaldehyde treatments. Unexpectedly, the treatments do not induce increased base substitution and short insertion/deletion mutagenesis, nor the appearance of the alcohol-associated cancer mutation signature SBS16. In contrast, we observe large genomic alterations in most cell lines, which parallel the association of 32 kb to 1 Mb deletions and duplications with alcohol consumption in a Japanese gastric cancer cohort. Observations of DNA damage response and a specific requirement for the homologous recombination pathway to tolerate acetaldehyde suggest that DNA breaks are responsible for structural genomic alterations in both cell line and tumour samples, and these may contribute to the carcinogenic effect of acetaldehyde.

Acetaldehyde treatment and whole genome sequencing of human cells reveal no increased base substitution mutagenesis but an induction of structural genomic alterations mirrored by the association of similar events with alcohol consumption in cancer.