The micropapillary subtype of urothelial carcinoma of the bladder (MPUC) is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contain activating mutations in the extracellular domain (ECD) of ERBB2.
We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations (GA) that have been associated with tumor progression and therapeutic response. 5,485 cases of archived formalin-fixed, paraffin embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and to evaluate the frequencies of GA. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 36.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared to non-MPUC were KMT2D, RB1 and MTAP alterations. KMT2D and RB1 are tumor suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.4%) in contrast to non-MPUC (27.6%) (p < 0.001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than non-MPUC (17.3%) (p = 0.012). Lastly, MTAP loss, an emerging biomarker for new synthetic lethality based anti-cancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than non-MPUC (26.9%) (p = 0.018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC, but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2024 Jan 12 [Epub ahead of print]
Jessica M Posada, Evgeny Yakirevich, Ashish M Kamat, Akshay Sood, Joseph M Jacob, Gennady Bratslavsky, Petros Grivas, Philippe E Spiess, Roger Li, Andrea Necchi, Anthony E Mega, Dragan J Golijanin, Dean Pavlick, Richard S P Huang, Douglas Lin, Natalie Danziger, Ethan Sokol, Smruthy Sivakumar, Jeffrey S Ross, Liang Cheng
Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI, USA., Department of Urology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Urology, The James Cancer Hospital and Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA., Upstate Medical University, Syracuse, NY, USA., Fred Hutchinson Cancer Center; University of Washington, Seattle, WA, USA., Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA., San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy., Division of Hematology and Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Providence, RI, USA., Division of Urology, Department of Surgery, Brown University, The Miriam Hospital, Providence, RI, USA., Foundation Medicine Inc., Cambridge, MA, USA., Upstate Medical University, Syracuse, NY, USA; Foundation Medicine Inc., Cambridge, MA, USA. Electronic address: ., Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/38219954