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.
iScience. 2020 May 27 [Epub ahead of print]
Guoliang Yang, Jolanta Bondaruk, David Cogdell, Ziqiao Wang, Sangkyou Lee, June Goo Lee, Shizhen Zhang, Woonyoung Choi, Yan Wang, Yu Liang, Gang Wang, Ying Wang, Hui Yao, Vipulkumar Dadhania, Jianjun Gao, Christopher Logothetis, Arlene Siefker-Radtke, Ashish Kamat, Colin Dinney, Dan Theodorescu, Marek Kimmel, Peng Wei, Charles C Guo, John N Weinstein, David J McConkey, Bogdan Czerniak
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CA, USA., Department of Statistics, Rice University, Houston, TX, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: .