Joint Effects of ALDH2 rs671 and Pathogenic Germline Variants in DNA Repair Genes on Risk of Aerodigestive and Gastrointestinal Cancers

BACKGROUND: The aldehyde dehydrogenase 2 (ALDH2) rs671 (G>A) variant, common in East Asians, impairs aldehyde detoxification. Pathogenic germline variants (PGVs) in homologous recombination repair (HRR) and mismatch repair (MMR) genes confer inherited susceptibility; however, their joint effects with rs671 remain poorly characterized. METHODS: We conducted a case-control study of 4,418 cases of head and neck, esophageal, gastric, or colorectal cancer and 11,811 controls. Targeted sequencing identified HRR and MMR PGVs. Associations and interactions were assessed using Firth-penalized logistic regression, stratified by alcohol intake. Cumulative risk was estimated using Japanese population incidence data. RESULTS: HRR PGV carriers with the rs671 GA/AA genotype showed increased risk across all cancer sites compared with rs671 GG non-carriers. Joint effects were observed among drinkers for head and neck, esophageal, and gastric cancers, and among non-drinkers for gastric and colorectal cancers. Among MMR PGV carriers, rs671 GA/AA was associated with increased risk of esophageal and colorectal cancers (odds ratio, 95.62 and 24.57, respectively), with significant interactions (P = 0.017 and 0.0011, respectively). The rs671-MMR association for esophageal cancer was evident among drinkers, whereas colorectal cancer risk was elevated in both drinkers and non-drinkers. By age 80, cumulative risk (95% confidence interval) among MMR PGV carriers with rs671 GA/AA was 35.4% (7.7-90.3) for esophageal and 87.7% (46.9-99.9) for colorectal cancer. CONCLUSIONS: Impaired aldehyde detoxification and DNA repair deficiency jointly increase site-specific cancer risk. IMPACT: Integrating ALDH2 rs671 genotype, DNA repair PGVs, and alcohol exposure may improve risk stratification and prevention in East Asian populations.