ADH1B - ALDH2 genotype combinations, Age-Related Risk, and Field Cancerization in Head and Neck and Upper GI Cancer Screening in 10,073 Alcohol-Dependent Men

Abstract 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 (OR 95%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 = 0.008). ORs by genotype combination did not differ significantly across screening-year periods or by invasive status. Multiple cancers 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.