Urothelial Cancers with Small Cell Variant Histology Have Confirmed High Tumor Mutational Burden, Frequent TP53 and RB Mutations, and a Unique Gene Expression Profile.

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis.

We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. PATIENT SUMMARY: Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity.

European urology oncology. 2020 Feb 12 [Epub ahead of print]

Jean Hoffman-Censits, Woonyoung Choi, Sumanta Pal, Edouard Trabulsi, William Kevin Kelly, Noah M Hahn, David McConkey, Eva Comperat, Andres Matoso, Oliver Cussenot, Geraldine Cancel-Tassin, Megan Hoi Yan Fong, Jeffrey Ross, Russell Madison, Siraj Ali

Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Department of Urology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA. Electronic address: ., The James Buchanan Brady Urological Institute, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA., Department of Medical Oncology and Therapeutics Research, City of Hope Cancer Center, Duarte, CA, USA., Department of Urology, The Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, USA., Department of Medical Oncology, The Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, USA., Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Department of Urology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA., Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA., CeRePP, Paris, France; Sorbonne Universite, GRC n°5, AP-HP, Hopital Tenon, Paris, France., Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA., Foundation Medicine, Inc., Cambridge, MA, USA.

Read an Expert Commentary by Bishoy Faltas, MD 

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