ADH1B-ALDH2 genotype combinations, age-related risk, and field cancerization in head and neck and upper GI cancer...

We analyzed initial endoscopic screening results, including esophageal iodine staining and oropharyngolaryngeal inspection, from 10 073 Japanese alcohol-dependent men (30-79 years) between 1993 and 2025. After adjustment for age, drinking and smoking habits, and screening year, using ADH1B*2 (rs1229984) plus ALDH2*1/*1 as the reference, the cancer risk (odds ratio (OR) [95% confidence interval (CI)]) associated with slow-metabolizing ADH1B*1/*1 plus ALDH2*1/*1, ADH1B*2 plus inactive ALDH2*2 (rs671), and ADH1B*1/*1 plus ALDH2*2 increased synergistically: 3.06 (2.13-4.39), 10.2 (7.33-14.2), and 21.0 (14.5-30.3) for esophageal squamous cell carcinoma (ESCC; n = 309, detection rate 3.1%); 4.34 (2.24-8.41), 11.3 (5.99-21.4), and 27.4 (14.3-52.5) for head and neck squamous cell carcinoma (HNSCC; n = 95, 0.9%). ADH1B*2 plus ALDH2*2 increased the OR for gastric adenocarcinoma (GA) to 3.71 (2.19-6.30; n = 91, 0.9%). ESCC and HNSCC were already detected at ages 30-39 (ESCC 0.3%, HNSCC 0.6%) and 40-49 (ESCC 1.3%, HNSCC 0.5%), and the corresponding ORs were markedly high in the 30-49 age group: 12.1 (2.62-56.0), 20.5 (4.09-103), and 166 (37.9-730) for ESCC; and 11.8 (1.36-102), 26.4 (2.92-238), and 95.0 (11.5-786) for HNSCC. The age-gradient difference in ORs was significant for ESCC (P = .008). ORs by genotype combination did not differ significantly across screening-year periods or by invasive status. Multiple cancers were detected in 39.8% of ESCC, 52.6% of HNSCC, and 30.8% of GA. Inactive ALDH2*2 was consistently linked with cancer multiplicity: ESCC OR 2.96 (1.77-4.95), HNSCC OR 14.0 (3.93-49.8), and GA OR 5.41 (1.63-18.0). These results support genotype-informed public health interventions in heavy-drinking East Asian populations.