摘要：SummaryWe 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 ofTP53and were dominated by Sanger mutation signature 3 associated with loss ofBRCA1/2function. 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.Graphical AbstractDisplay OmittedHighlights•SCCs show TP53/RB1 loss with mutational signature of BRCA1/2 loss of function•SCCs are driven by neural phenotypic switch with dysregulated EMT network•SCCs show depleted immune phenotype with upregulation of ADORA2ABiological Sciences; Genomics; Cancer Systems Biology; Cancer; Transcriptomics
