Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Int J Cancer. 2019 Mar 1;144(5):1160-1169. doi: 10.1002/ijc.31755. Epub 2018 Oct 16.
Treatment modalities in esophageal squamous cell carcinoma (ESCC) depend largely on lymph node metastasis (LNM) status. With suboptimal detection sensitivity of existing imaging techniques, we propose a methylation signature which identifies patients with LNM with greater accuracy. This would allow precise stratification of high-risk patients requiring more aggressive treatment from low-risk ESCC patients who can forego radical surgery. An unbiased genome-wide methylation signature for LNM detection was established from an initial in silico discovery phase. The signature was tested in independent clinical cohorts comprising of 249 ESCC patients. The prognostic potential of the methylation signature was compared to clinical variables including LNM status. A 10-probe LNM associated signature (LNAS) was developed using stringent bioinformatics analyses. The area under the curve values for LNAS risk scores were 0.81 and 0.88 in the training and validation cohorts respectively, in association with lymphatic vessel invasion and tumor stage. High LNAS risk-score was also associated with worse overall survival [HR (95% CI) 3 (1.8-4.8), p < 0.0001 training and 3.9 (1.5-10.2), p = 0.001 validation cohort]. In conclusion, our novel methylation signature is a powerful biomarker that identifies LNM status robustly and is also associated with worse prognosis in ESCC patients.
治疗食管鳞状细胞癌（ESCC）的方法在很大程度上取决于淋巴结转移（LNM）状态。由于现有成像技术的检测灵敏度不理想，我们提出了一种甲基化特征，可以更准确地识别有 LNM 的患者。这将允许对需要更积极治疗的高危患者进行精确分层，而对于低危 ESCC 患者可以避免根治性手术。从初始的计算机发现阶段建立了用于 LNM 检测的无偏基因组甲基化特征。该特征在由 249 名 ESCC 患者组成的独立临床队列中进行了测试。将甲基化特征的预后潜力与包括 LNM 状态在内的临床变量进行了比较。使用严格的生物信息学分析开发了一个 10 个探针与 LNM 相关的特征（LNAS）。在训练和验证队列中，LNAS 风险评分的曲线下面积值分别为 0.81 和 0.88，与淋巴管浸润和肿瘤分期相关。高 LNAS 风险评分也与总体生存较差相关[风险比（95%置信区间）3（1.8-4.8），p < 0.0001 训练队列和 3.9（1.5-10.2），p = 0.001 验证队列]。总之，我们的新型甲基化特征是一种强大的生物标志物，可可靠地识别 LNM 状态，并且与 ESCC 患者的预后较差相关。
