Multi-Omics Studies On Esophageal Squamous Cell Carcinoma And Its Precursor

Background:Esophageal cancer is the 4th leading cause of caucer death in China.Primary small cell carcinoma of the esophagus(PSCCE)is one of deadliest neuroendocrine subtype with increasing prevaleince.Treatment approaches were extrapolated from small cell lung cancer(SCLC)but no consensus was reached.Previous studies proposed genetic similarity of PSCCE to esophageal squamous cell carcinoma(ESCC),but failed to explain differences in neuroendocrine differentiation,disease course and immunohistochemistry between PSCCE and ESCC.Knowledge of therapeutic targets was lacking.We sought to identify potential drivers,describe molecular subtypes and dissect tumor microenvironment of PSCCE by integrated multi-omics profiling.Methods:We performed whole exome sequencing,RNA sequencing and immune profiling on 46 PSCCE.We integrated multi-omics data and compared with published sequencing studies.Results:We discovered high frequency inactivation of TP53(85%)and RB1(98%).Other drivers included NOTCH1,EP300 and FBXW7.RB1 was inactivated by multiple mechanisms including genomic alterations,splicing abnormalities and complete loss of protein.Notch signaling pathway was inactivation in PSCCE.Transcriptomic feature of PSCCE highly resembled SCLC and presented novel therapeutic targets.We discovered two distinct molecular subtypes of PSCCE featured by differential expression of lineage transcription factor ASCL1(PSCCE-A)and NEUROD1(PSCCE-N),highly similar to subtypes of SCLC.Immune profiling revealed insufficient T cell infiltration and immune"excluded" as the predominant immune phenotype.Conclusions:RB1 was inactivated by multiple mechanisms to an unanticipated high frequency.PSCCE had genetic bases and transcriptome features highly similar to SCLC,but not ESCC.Distinct transcriptomic landscape and immune microenvironment provided potential therapeutic targets.Background:The systemic immune-inflammation index(SII)has been reported to be associated with patient survival in various kinds of solid tumors.However,just few studies have focused on its prognostic value in patients with surgically resected esophageal squamous cell carcinoma(ESCC).Methods:This study was a single-institution,retrospective analysis of 468 ESCC patients who underwent curative esophagectomy at the Department of Thoracic Surgery,National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College between 2005 and 2008.The receiver operating curve(ROC)was plotted to compare the discrimination ability of the SII and other inflammatory factors for overall survival(OS)and disease-free survival(DFS).Univariate and multivariate analyses were performed based on the Cox proportional hazards regression model.Results:The SII,neutrophil-lymphocyte ratio(NLR),and platelet-lymphocyte ratio(PLR)were all associated with OS in ESCC patients.The SII,NLR,and PLR were independent prognostic factors for OS(hazard ratio(HR)=1.604,95%confidence interval(CI)1.247-2.063,P<0.001;HR=1.396,95%CI 1.074-1.815,P=0.013;HR=1.370,95%CI 1.067-1.758,P=0.013,respectively)and DFS(HR=1,681,95%CI 1.307-2.162,P<0.001;HR=1.376,95%CI 1.059-1.788,P=0.017;HR=1.398,95%CI 1.089-1.794,P=0.009,respectively).The area under the curve(AUC)for SII was bigger than NLR,PLR,and MLR(0.553,0.540,0.532,and 0.521,respectively).Conclusion:The SII is a simple and promising prognostic predictor for patients with surgically resected ESCC.The prognostic value of SII is superior to those of the NLR,PLR and MLR.Moreover,the SII retained prognostic significance in stage Ⅰ-Ⅱ ESCC subgroup(OS,DFS)and stage Ⅲ ESCC subgroup(DFS).