By integrating multi-omics data, we revealed the following findings: (1) PSCCE harbors a high frequency (98%) of RB1 disruption mediated by multiple mechanisms; (2) the transcriptome of PSCCE highly resembles that of SCLC, but not that of ESCC or EAC; (3) PSCCE has two distinct subtypes regulated by lineage TFs ASCL1 and NEUROD1; and (4) insufficient T-cell infiltration is widely observed in PSCCE. The gene discussed is ASCL1; the disease is esophageal squamous cell carcinoma.