A comprehensive methylation signature identifies lymph node metastasis in esophageal squamous cell carcinoma

Abstract

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.

Aberrant DNA Methylation in Esophageal Squamous Cell Carcinoma: Biological and Clinical Implications

“…Using DNA from the plasma of ESCC patients, Liu et al analyzed the methylation status of Wnt antagonists SFRP1, DKK3, and RUNX3 and showed that patients carrying two or three of these hypermethylated genes had a significantly elevated risk of cancer recurrence, compared with those without methylated genes (46). In an attempt to identify DNA methylation markers in predicting lymph node metastasis, the genome-wide methylation of 86 ESCC patients has been recently assessed, and a 10-probe lymph node metastasis-associated methylation signature has been established through stringent bioinformatics analyses (83). All in all, finding genes of prognostic impact aberrantly methylated allows one to customize therapy for ESCC patients: patients with a worse prognosis might benefit from a more aggressive treatment strategy, while patients with low risk can forego radical surgery.…”

Identification of DNA methylation-driven genes in esophageal squamous cell carcinoma: a study based on The Cancer Genome Atlas

“…In recent years, studies on methylation and tumors have gradually drawn more attention. For instance, Roy et al analyzed the lymph node metastasis in esophageal squamous cell carcinoma and built a comprehensive methylation signature for predicting the prognosis of patients [8]. Genes including NNK, MSH3 and P16, which were stated to be methylated, associated with tumors progression [9–11].…”

ECM Remodeling in Squamous Cell Carcinoma of the Aerodigestive Tract: Pathways for Cancer Dissemination and Emerging Biomarkers

“…Among the various clinical risk factors associated with ESCC pathogenesis, lymph node metastasis significantly contribute to poor prognosis, with the overall 5-year survival rates post-surgery dropping from 70–92% to 18–47% in patients with LNM [ 48 ]. Hence, the accurate identification of the LNM status, by imaging and molecular approaches, plays a crucial role in determining treatment strategies as well as prognostic outcomes [ 49 ]. In ESCC, the colonization of lymph nodes by metastatic cells is dependent on the primary tumor site, the T-stage, and the tumor histotype [ 50 ].…”