Background/Objectives: Esophageal and esophagogastric junction adenocarcinoma (EADC-EGJA), which mainly develops from Barrett’s esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), has a poor prognosis and several unmet clinical needs, among which is the detection of minimal residual disease (MRD) after endoscopic/surgical resection. Long interspersed nuclear element-1 (LINE-1), a surrogate marker of global methylation, is considered an emerging biomarker for MRD monitoring. The aim of this study was to determine, by LINE-1 methylation analysis, at which carcinogenesis step global methylation is affected and whether this biomarker could be followed in longitudinal to monitor the disease behavior post-surgery.Methods: Cell-free DNA of 90 patients with non-dysplastic Barrett’s esophagus (NDBE), HGD/early EADC-EGJA, or locally advanced/advanced EADC-EGJA were analyzed for LINE-1 methylation, by Methylation-Sensitive Restriction Enzyme droplet digital PCR (MSRE-ddPCR). Twenty-six patients were longitudinally studied by repetitive blood sampling.Results: Global hypomethylation increased during carcinogenesis, with significant difference between locally advanced/advanced EADC-EGJA and NDBE patients (p= 0.028). Longitudinal cases confirmed the rareness of hypomethylation in NDBE cases. The majority of HGD/early EADC-EGJA and locally advanced/advanced EADC-EGJA patients showed methylation changes after resection according to clinical status.Conclusions: This study suggests that global hypomethylation occurs just prior to cancer invasiveness and that it is a promising biomarker to monitor MRD.
背景/目的：食管及食管胃结合部腺癌主要起源于巴雷特食管、低级别上皮内瘤变和高级别上皮内瘤变，其预后较差且存在多项未满足的临床需求，其中术后微小残留病灶的检测是亟待解决的问题之一。长散布核元件-1作为全基因组甲基化的替代标志物，被认为是监测微小残留病灶的新兴生物标志物。本研究旨在通过长散布核元件-1甲基化分析，明确全基因组甲基化在癌变过程的哪个阶段发生改变，并验证该生物标志物能否通过纵向监测追踪术后疾病进展。 方法：采用甲基化敏感限制性内切酶微滴数字PCR技术，对90例非异型增生性巴雷特食管、高级别上皮内瘤变/早期食管及食管胃结合部腺癌、局部进展期/晚期食管及食管胃结合部腺癌患者的游离DNA进行长散布核元件-1甲基化分析。其中26例患者通过重复采血进行纵向研究。 结果：全基因组低甲基化水平在癌变过程中逐渐升高，局部进展期/晚期食管及食管胃结合部腺癌患者与非异型增生性巴雷特食管患者之间存在显著差异。纵向研究证实非异型增生性巴雷特食管病例中低甲基化现象较为罕见。根据临床状态评估，大多数高级别上皮内瘤变/早期食管及食管胃结合部腺癌及局部进展期/晚期食管及食管胃结合部腺癌患者在切除术后呈现甲基化水平变化。 结论：本研究表明全基因组低甲基化现象恰发生于癌症侵袭阶段之前，是监测微小残留病灶的潜在生物标志物。
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