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

iScience

John N. Weinstein¹  Hui Yao²  David J. McConkey²  Ziqiao Wang³  Ying Wang³  Peng Wei³  Arlene Siefker-Radtke⁴  Jianjun Gao⁴  Christopher Logothetis⁴  Guoliang Yang⁵  Sangkyou Lee⁵  June Goo Lee⁵  Vipulkumar Dadhania⁵  David Cogdell⁵  Charles C. Guo⁵  Yu Liang⁵  Gang Wang⁵  Jolanta Bondaruk⁵  Shizhen Zhang⁵  Yan Wang⁵  Marek Kimmel⁶  Ashish Kamat⁷  Colin Dinney⁷  Woonyoung Choi⁸  Bogdan Czerniak⁸  Dan Theodorescu⁹ 

[1] Corresponding author;Department of Bioinformatics and Computational Biology, 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;Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Statistics, Rice University, Houston, TX, USA;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA;Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CA, USA;

关键词: Biological Sciences;    Genomics;    Cancer Systems Biology;    Cancer;    Transcriptomics;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

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