Kagemoto Kenichi, Urabe Yuji, Miwata Tomohiro, Oka Shiro, Ochi Hidenori, Kitadai Yasuhiko, Tanaka Shinji, Chayama Kazuaki
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.
Cancer Med. 2016 Jul;5(7):1397-404. doi: 10.1002/cam4.705. Epub 2016 Mar 31.
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.
先前的一项全基因组关联研究确定了两个新的食管鳞状细胞癌（ESCC）易感基因，即ADH1B和ALDH2。我们研究了ESCC的特征，以及异时性食管和/或咽鳞状细胞癌（SCC）与ADH1B和ALDH2风险等位基因之间的关系。对117例行内镜黏膜下剥离术（ESD）治疗的浅表性ESCC患者进行了≥12个月的内镜随访。首先，我们进行了一项重复分析，使用117例浅表性ESCC病例和1125例健康对照来确认ESCC与ADH1B和ALDH2风险等位基因之间的关系。接下来，我们调查了ESD后异时性SCC发生的发生率及相关遗传/环境因素。我们还使用Cox比例风险模型分析了异时性SCC发生的潜在风险因素。位于ADH1B上的rs1229984 GG和位于ALDH2上的rs671 GA与ESCC进展显著相关（P = 7.93×10⁻⁴和P = 1.04×10⁻⁵）。携带rs1229984 GG的患者、携带rs671 GA的患者、吸烟者、重度饮酒者（每天摄入44克乙醇）以及存在多个不染碘病变（LVL）的患者更频繁地发生异时性SCC（P分别为3.20×10⁻³、7.00×10⁻⁴、4.00×10⁻⁴、2.15×10⁻²和4.41×10⁻³），风险比分别为2.84（95%置信区间[CI]=1.43 - 5.63）、4.57（95% CI = 1.80 - 15.42）、4.84（95% CI = 1.89 - 16.41）和2.34（95% CI = 1.12 - 5.31）。多因素logistic回归分析显示，rs1229984 GG rs671 GA和吸烟状态与ESD后发生异时性SCC的风险独立相关。此外，我们发现这两个遗传因素（rs1229984 GG和rs671 GA）和一个环境因素（吸烟）的累积效应似乎使ESCC风险的ESD后异时性SCC增加了近12倍。我们的研究结果阐明了ADH1B和ALDH2中多个基因变异作为异时性ESCC生物标志物的关键作用。
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