Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

Authors: Charles C. Guo,^1,8 Tadeusz Majewski,^1,8 Li Zhang,^2,8 Hui Yao,³ Jolanta Bondaruk,¹ Yan Wang,¹ Shizhen Zhang,¹ Ziqiao Wang,⁴ June Goo Lee,¹ Sangkyou Lee,¹ David Cogdell,¹ Miao Zhang,¹ Peng Wei,⁴ H. Barton Grossman,⁵ Ashish Kamat,⁵ Jonathan James Duplisea,⁵ James Edward Ferguson III,⁵ He Huang,¹ Vipulkumar Dadhania,¹ Jianjun Gao,⁶ Colin Dinney,⁵ John N. Weinstein,³ Keith Baggerly,³ David McConkey,⁷ and Bogdan Czerniak¹

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA
Department of Bioinformatics & 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 Urology, 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
Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA

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