Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2

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 S Sokol; Smruthy Sivakumar; Jeffrey S Ross; Liang Cheng

doi:10.1016/j.modpat.2024.100424

Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2

Mod Pathol. 2024 Mar;37(3):100424. doi: 10.1016/j.modpat.2024.100424. Epub 2024 Jan 12.

Authors

Jessica M Posada¹, Evgeny Yakirevich², Ashish M Kamat³, Akshay Sood⁴, Joseph M Jacob⁵, Gennady Bratslavsky⁵, Petros Grivas⁶, Philippe E Spiess⁷, Roger Li⁷, Andrea Necchi⁸, Anthony E Mega⁹, Dragan J Golijanin¹⁰, Dean Pavlick¹¹, Richard S P Huang¹¹, Douglas Lin¹¹, Natalie Danziger¹¹, Ethan S Sokol¹¹, Smruthy Sivakumar¹¹, Jeffrey S Ross¹², Liang Cheng¹³

Affiliations

¹ 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, Rhode Island; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, New York.
² 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, Rhode Island.
³ Department of Urology, the University of Texas MD Anderson Cancer Center, Houston, Texas.
⁴ Department of Urology, The James Cancer Hospital and Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio.
⁵ Upstate Medical University, Syracuse, New York.
⁶ Fred Hutchinson Cancer Center, University of Washington, Seattle, Washington.
⁷ Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida.
⁸ San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
⁹ Division of Hematology and Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Providence, Rhode Island.
¹⁰ Division of Urology, Department of Surgery, Brown University, The Miriam Hospital, Providence, Rhode Island.
¹¹ Foundation Medicine Inc., Cambridge, Massachusetts.
¹² Upstate Medical University, Syracuse, New York; Foundation Medicine Inc., Cambridge, Massachusetts. Electronic address: jross@foundationmedicine.com.
¹³ 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, Rhode Island. Electronic address: liang_cheng@brown.edu.

PMID: 38219954
DOI: 10.1016/j.modpat.2024.100424

Abstract

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. 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 39.7%, 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 with 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 (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .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.

Keywords: ERBB2/HER2; bladder; micropapillary subtype; molecular genetics; targeted therapy; urothelial carcinoma.

MeSH terms

Biomarkers, Tumor / genetics
Carcinoma, Transitional Cell* / genetics
Carcinoma, Transitional Cell* / pathology
Genomics
Humans
Mutation
Receptor, ErbB-2 / genetics
Urinary Bladder / pathology
Urinary Bladder Neoplasms* / genetics
Urinary Bladder Neoplasms* / pathology

Substances

Biomarkers, Tumor
ERBB2 protein, human
Receptor, ErbB-2