History of Alcohol‐Related Cancers and ADH1B/ALDH2 Genotypes in a Large Japanese Cohort of Male Patients With Alcohol Dependence

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BACKGROUND: Alcohol-dependent (AD) patients frequently present with a history of alcohol-related cancers, but the timing of cancer treatment relative to the onset of advanced alcohol use disorder and the role of ADH1B/ALDH2 genotypes remain unclear. METHODS: We reviewed cancer histories at the initial visit of 5214 Japanese male AD patients (mean age 53.3 [SD 11.9] years), all genotyped for ADH1B (rs1229984) and ALDH2 (rs671). Multiple logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for site-specific cancers, using fast-metabolizing ADH1B*2 and active ALDH2*1/*1 as the reference. RESULTS: Alcohol-related cancers were reported in 385 patients (7.38%): head and neck cancer (HNC) 1.05%, esophageal cancer (EC) 1.40%, gastric cancer (GC) 3.91%, colorectal cancer (CRC) 1.53%, and liver cancer (LC) 0.59%. Surgical treatment rates were high across sites. Most cancers were treated during or after the onset of advanced alcohol use disorder (HNC 81.8%, EC 74.0%, GC 48.5%, CRC 63.8%, and LC 87.1%). The slow-metabolizing ADH1B*1/*1 genotype was associated with high ORs for HNC (1.99; 95% CI 1.14-3.47) and EC (3.05; 1.87-4.99), but low ORs for GC (0.65; 0.45-0.95) and gastrectomy for peptic ulcer disease (0.59; 0.38-0.92). Gastrectomy, common among GC cases, accelerates alcohol delivery to the small intestine, increasing peak blood alcohol levels and exposure, and may offset the AD risk associated with ADH1B*1/*1. The inactive ALDH2*2 allele conferred elevated ORs for HNC (8.63; 4.90-15.21), EC (11.35; 6.78-18.99), GC (1.54; 1.08-2.19), and CRC (1.72; 1.01-2.91). The combined genotype (ADH1B*1/*1 and ALDH2*2) substantially increased ORs for HNC (17.05; 8.17-35.59) and EC (35.03; 17.38-70.65). Multiorgan cancerization was common along the digestive tract. The combined genotype increased ORs for multiorgan cancerization in HNC and EC, and ALDH2*2 increased ORs in GC and CRC. CONCLUSION: Genotype strongly influences alcohol-related cancer risk, and many cancers occur during or after advanced alcohol use disorder.

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