A multicenter prospective clinical trial reveals cell-free DNA methylation markers for early esophageal cancer

BACKGROUND. Current methods for detecting esophageal cancer (EC) are generally invasive or exhibit limited sensitivity and specificity, especially for the identification of early-stage tumors. METHODS. We identified potential methylated DNA markers (MDMs) from multiple genomic regions in a discovery cohort, and a diagnostic model was developed and verified in a model-verification cohort of 297 participants. The accuracy of the MDM panel was validated in a multicenter, prospective cohort (n = 1,429). The clinical performance of identified MDMs were compared with current tumor-associated protein markers. RESULTS. From 31 significant differentially methylated EC-associated regions identified in the marker discovery, we trained and validated a 3-MDM diagnostic model that could discriminate among patients with EC and volunteers without EC in a multicenter clinical prospective cohort with a sensitivity of 85.5% and a specificity of 95.3%. This panel showed higher sensitivity in diagnosing early-stage tumors, with sensitivities of 56% for stage 0 and 77% for stage I, compared with the performance of current biochemical markers. In population with high risk for EC, the sensitivity and specificity were 85.68% and 93.61%, respectively. CONCLUSION. The assessment of tumor-associated methylation status in blood samples can facilitate noninvasive and reliable diagnosis of early-stage EC, which warrants further development to expand screening and reduce mortality rates.