ADH1B and ALDH2 are associated with metachronous SCC after endoscopic submucosal dissection of esophageal squamous cell carcinoma

Abstract

A previous genome-wide association study identified two novel esophageal squamous cell carcinoma (ESCC) susceptibility genes, ADH1B and ALDH2. We investigated the characteristics of ESCC, and the relationship between metachronous esophageal and/or pharyngeal squamous cell carcinoma (SCC) and the ADH1B & ALDH2 risk alleles. One hundred and seventeen superficial ESCC patients who underwent treatment with endoscopic submucosal dissection (ESD) were followed up using endoscopy for ≥12 months. First, we performed a replication analysis to confirm the relationship between ESCC and the ADH1B & ALDH2 risk alleles using 117 superficial ESCC cases and 1125 healthy controls. Next, we investigated the incidence and genetic/environmental factors associated with metachronous SCC development after ESD. We also analyzed the potential risk factors for metachronous SCC development using Cox's proportional hazards model. rs1229984 GG located on ADH1B and rs671 GA located on ALDH2 were significantly associated with ESCC progression (P = 7.93 × 10⁻⁴ and P = 1.04 × 10⁻⁵). Patients with rs1229984 GG, those with rs671 GA, smokers, heavy alcohol drinkers (44 g/day ethanol), and presence of multiple Lugol-voiding lesions (LVLs) developed metachronous SCC more frequently (P = 3.20 × 10⁻³, 7.00 × 10⁻⁴, 4.00 × 10⁻⁴, 2.15 × 10⁻², and 4.41 × 10⁻³, respectively), with hazard ratios were 2.84 (95% confidence interval [CI] = 1.43–5.63), 4.57 (95% CI = 1.80–15.42), 4.84 (95% CI = 1.89–16.41), and 2.34 (95% CI = 1.12–5.31), respectively. Multiple logistic regression analysis revealed that rs1229984 GG, rs671 GA, and smoking status were independently associated with the risk of developing metachronous SCCs after ESD. Moreover, we found cumulative effects of these two genetic factors (rs1229984 GG and rs671 GA) and one environmental factor (tobacco smoking) which appear to increase metachrous SCCs after ESD of ESCC risk approximately nearly 12-fold. Our findings elucidated the crucial role of multiple genetic variations in ADH1B and ALDH2 as biomarkers of metachronous ESCC.

The main contribution of our paper is the characteristics of esophageal squamous cell carcinoma (ESCC), and the relationship between metachronous esophageal and/or pharyngeal squamous cell carcinoma (SCC) and the ADH1B & ALDH2 risk alleles. We show that rs1229984, rs671, and smoking status are independently associated with the risk of developing metachronous SCCs. In addition, individuals with three risk factors have a 11.95-fold higher risk for metachrous SCCs than those with no or one risk factors, indicating the cumulative effects of these variations.

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