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

Charles Chuanhai Guo; Tadeusz Majewski; Li Zhang; Hui Yao; Jolanta E. Bondaruk; Yan Wang; Shizhen Zhang; Ziqiao Wang; June Goo Lee; Sangkyou Lee; David E. Cogdell; Miao Zhang; Peng Wei; H. Barton Grossman; Ashish M. Kamat; Jonathan J. Duplisea; James E. Ferguson; He Huang; Vipulkumar Dadhania; Jianjun Gao; Colin P. Dinney; John N. Weinstein; Keith Baggerly; David James McConkey; Bogdan A. Czerniak

doi:10.1016/j.celrep.2019.04.048

GenomicsCell ReportsMay 1, 2019

Peer-reviewed journal article

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

Charles Chuanhai Guo iD, Tadeusz Majewski iD, Li Zhang iD, Hui Yao iD, Jolanta E. Bondaruk, Yan Wang iD, Shizhen Zhang iD, Ziqiao Wang iD, June Goo Lee, Sangkyou Lee, David E. Cogdell, Miao Zhang iD, Peng Wei iD, H. Barton Grossman, Ashish M. Kamat iD, Jonathan J. Duplisea, James E. Ferguson iD, He Huang iD, Vipulkumar Dadhania, Jianjun Gao iD, Colin P. Dinney iD, John N. Weinstein iD, Keith Baggerly, David James McConkey iD, Bogdan A. Czerniak iD

Abstract

The sarcomatoid variant of 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 SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment of TP53, RB1, and PIK3CA mutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited 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.

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