Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. The exomes of more than 600 ESCCs have been sequenced in the last 4 years, and numerous key aberrations have been identified1-4. Recently, researchers reported both inter- and intra-tumor heterogeneity5, 6. Although these are interesting observations, their clinical implications are unclear due to limited number of samples profiled. Epigenomic alterations, such as changes in DNA methylation, histone acetylation, and RNA editing, have also been observed in ESCCs.