title: 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.
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kagemoto
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.|Department of Regeneration and Medicine Medical center for Translation and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Urabe
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miwata
authors.affiliation: Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Oka
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kitadai
authors.affiliation: Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics*; D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000209:etiology* / Q000473:pathology; D016022:Case-Control Studies; D000069916:Endoscopic Mucosal Resection / Q000379:methods; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000209:etiology* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000175:diagnosis* / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase; C096127:ALDH2 protein, human; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: ADH1B; ALDH2; endoscopy; esophageal squamous cell carcinoma; metachronous