Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-24043-6
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Funding
- National Key R&D Program of China [2018YFC1312100, 2017YFC1311000, 2018YFC1313100, 2019YFC1315700]
- National Natural Science Foundation of China [81972316]
- Beijing Nova Program [Z181100006218032]
- Beijing Hope Run Special Fund of Cancer Foundation of China [LC2017A14]
- CAMS Initiative for Innovative Medicine (CIFMS) [2017-I2M-1-005, 2017-I2M-2-003, 2016-I2M-1-001]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320022]
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Primary small cell carcinoma of the esophagus (PSCCE) shares genetic similarities with esophageal squamous cell carcinoma (ESCC) but has distinct genomic alterations, transcriptome features, and molecular subtyping similar to small cell lung cancer (SCLC). RB1 disruptions are frequent in PSCCE cases. This study provides insights into potential therapeutic strategies for treating PSCCE.
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. Primary small cell carcinoma of the oesophagus has a poor prognosis, and has not been fully characterised molecularly. Here, the authors study the disease using multi-omics technology and find frequent RB1 disruptions and similarities to small cell lung cancer, opening potential therapeutic avenues.
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