Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer.

IScience
Guoliang YangBogdan Czerniak

Abstract

We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with The Cancer Genome Atlas cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation signature 3 associated with loss of BRCA1/2 function. SCCs were characterized by downregulation of luminal and basal markers and were referred to as double-negative. Transcriptome analyses indicated that SCCs displayed lineage plasticity driven by a urothelial-to-neural phenotypic switch with a dysregulated epithelial-to-mesenchymal transition network. SCCs were depleted of immune cells, and expressed high levels of the immune checkpoint receptor, adenosine receptor A2A (ADORA2A), which is a potent inhibitor of immune infiltration. Our observations have important implications for the prognostication and development of more effective therapies for this lethal bladder cancer variant.

Citations

Aug 11, 2021·Surgical Pathology Clinics·Hikmat Al-Ahmadie, George J Netto

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Datasets Mentioned

BETA
SUB6960718
GSE128277

Methods Mentioned

BETA
transfection
RNA-seq

Clinical Trials Mentioned

NCT02655822

Software Mentioned

CIBERSORT
IPA
Gene Set Enrichment Analysis ( GSEA )
Gene Set Enrichment Analysis
GSEA
Ingenuity Pathway Analysis ( IPA )

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