Causal association between alcohol consumption and lung cancer subtypes and the underlying dna methylation mechanisms
Menée à partir de données de randomisation mendélienne, cette étude analyse l'association entre des modifications de la méthylation de l'ADN induites par la consommation d'alcool et le risque de cancer du poumon par sous-type
PURPOSE: The causal role of alcohol consumption in lung cancer subtypes and its epigenetic mechanisms remain unclear. We investigated the association between alcohol consumption and lung cancer subtypes and explored alcohol-related DNA methylation mechanisms underlying lung squamous cell carcinoma (LUSC).
METHODS: We integrated evidence from Mendelian randomization (MR), population-based validation, and in vitro experiments. Meta-analyses of two-sample MR studies were used to assess genetically predicted alcohol consumption in relation to overall lung cancer and major histological subtypes. Alcohol-related methylation quantitative trait loci (mQTLs) were then applied to identify CpG sites potentially involved in LUSC risk. In UK Biobank, we tested whether mQTL genotypes for MR-prioritized CpG sites modified the association between alcohol consumption and LUSC. Finally, ethanol-treated human bronchial epithelial cells were used to validate methylation, gene-expression, tumor-marker, proliferation, and migration changes.
RESULTS: Genetically predicted alcohol consumption was associated with increased LUSC risk (OR=1.32, 95%CI: 1.06-1.63), but not consistently associated with overall lung cancer, lung adenocarcinoma, or small-cell lung cancer. Methylation MR identified TOP1MT cg12188860 and SMAD3 cg26430287 as candidate alcohol-related CpG sites, with higher methylation associated with lower LUSC risk (cg12188860: OR=0.90, 95%CI: 0.84-0.97, PFDR = 0.032; cg26430287: OR=0.88, 95%CI: 0.78-0.98, PFDR = 0.054). In UK Biobank, mQTL variants linked to cg12188860 and cg26430287 modified alcohol-associated LUSC risk, particularly among individuals with low smoking exposure. In this subgroup, rs35052796 C-allele carriers (CC+CT) had increased risk with moderate (OR=2.83, 95% CI: 1.15–7.00) and high alcohol intake (OR=5.27, 95% CI: 1.37–20.31; Pinteraction=0.043), while rs60428975 C-allele carriers had increased risk with high alcohol intake (OR=6.42, 95% CI: 2.39–17.29; Pinteraction=0.049). No association was observed among TT homozygotes at either locus. In vitro, ethanol exposure reduced methylation at both CpG sites, increased expression of TOP1MT, SMAD3, and LUSC-related markers, and enhanced proliferative and migratory capacity (P<0.05).
CONCLUSIONS: Alcohol exposure may increase LUSC risk through epigenetic dysregulation. Alcohol-related methylation changes at cg12188860 and cg26430287 may inform precision risk stratification and targeted alcohol-intervention strategies.
Annals of Epidemiology , article en libre accès, 2026