Multi-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes

Renda Li,Jie Wang,Zhenlin Yang,Susheng Shi,Sijin Sun,Yingli Sun,Shugeng Gao,Hong Sheng Cheng ,Fengwei Tan,Yibo Gao,Yin Li,Fan Zhang,Zitong Li,Yaru Wen,Wei Guo,Liyan Xue,Fengmin Shao ,Nan Bi,Qi Xue,Jie He

doi:10.1038/s41467-021-24043-6

Abstract

Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma. Previous studies proposed a genetic similarity between PSCCE and esophageal squamous cell carcinoma (ESCC) but provided little evidence for differences in clinical course and neuroendocrine differentiation. We perform whole-exome sequencing, RNA sequencing and immunohistochemistry profiling on 46 PSCCE cases. Integrated analyses enable the discovery of multiple mechanisms of RB1 disruption in 98% (45/46) of cases. The transcriptomic landscape of PSCCE closely resembles small cell lung cancer (SCLC) but differs from ESCC or esophageal adenocarcinoma (EAC). Distinct gene expression patterns regulated by ASCL1 and NEUROD1 define two molecular subtypes, PSCCE-A and PSCCE-N, which are highly similar to SCLC subtypes. A T cell excluded phenotype is widely observed in PSCCE. In conclusion, PSCCE has genomic alterations, transcriptome features and molecular subtyping highly similar to SCLC but distinct from ESCC or EAC. These observations are relevant to oncogenesis mechanisms and therapeutic vulnerability.

Highlights

Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma
In the integrated analysis of mutational signatures of PSCCE (n = 101, combined with 55 cases reported by Wang et al.[11], hereinafter referred to as the “combined cohort”), small cell lung cancer (SCLC) (n = 110, ref. 12), esophageal adenocarcinoma (EAC) (n = 88, TCGA), and esophageal squamous cell carcinoma (ESCC) (n = 96, TCGA), we identified five principal mutational signatures, E1–E5 (Fig. 1b), which were highly similar to Catalogue Of Somatic Mutations In Cancer (COSMIC) signatures 1, 13, 4, 16, and 17, respectively
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

Summary

Introduction

Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma. The transcriptomic landscape of PSCCE closely resembles small cell lung cancer (SCLC) but differs from ESCC or esophageal adenocarcinoma (EAC). PSCCE has genomic alterations, transcriptome features and molecular subtyping highly similar to SCLC but distinct from ESCC or EAC. These observations are relevant to oncogenesis mechanisms and therapeutic vulnerability. Integrated genomics and transcriptomics studies of SCLC converged on four distinct molecular subtypes each with unique susceptibilities to different targeted therapies[13,14,15], which was informative to future researches and clinical trials. These studies of SCLC inspired several studies on promising therapeutic targets, including the inhibition of Aurora kinase[14,16] and targeting metabolism addition of specific SCLC subtype[17]

Methods

Results

Conclusion