Veronika Weyerer1, Rebecca Weisser1, Evgeny A Moskalev1, Florian Haller1, Robert Stoehr1, Markus Eckstein1, Ulrike Zinnall1,2, Nadine T Gaisa3, Eva Compérat4, Aurel Perren5, Bastian Keck6,7, Yves Allory8, Glen Kristiansen9, Bernd Wullich6, Abbas Agaimy1, Arndt Hartmann1, Simone Bertz1. 1. Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 2. Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 3. Department of Pathology, RWTH Aachen University, Aachen, Germany. 4. Department of Pathology, Pitié-Salpétrière Hospital, UPMC, Paris, France. 5. Institute of Pathology, University of Bern, Bern, Switzerland. 6. Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 7. Private Practice for Urology, Erlangen, Germany. 8. Service de Pathologie, CHU Henri Mondor, Créteil, France. 9. Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Abstract
AIMS: Nested variant of urothelial carcinoma (NVUC) is rare, and only a few small series exist. Molecular characteristics and the classifying marker profile as well as therapeutic targets of this specific variant are mostly unknown. The aim of this study was to characterise NVUC at the molecular level in one of the largest cohorts to date. In addition, we applied an immunohistochemical marker panel in order to define the molecular subtype. METHODS AND RESULTS: Sixty NVUC cases were collected from different departments. TERT promoter mutation analysis was carried out in all samples using SNaPshot analysis. Targeted sequencing of 48 cancer-related genes by next-generation sequencing (NGS) analysis was performed in a subset of 26 cases. Immunohistochemical markers CD44, CK5, CK14, EGFR, p63, FOXA1, GATA3, CD24 and CK20 were used to elucidate the molecular subtype. A total of 62.5% of NVUC cases harboured a mutation of the TERT promoter. Additionally, TP53, JAK3 and CTNNB1 were among the most frequently mutated genes identified by NGS analysis. Subtyping revealed that all NVUC express luminal markers such as CD24, FOXA1, GATA3 and CK20. CONCLUSIONS: In summary, NVUC belong to the luminal molecular subtype. Moreover, a subset of NVUC seems to be characterised by mutations of the Wnt and inflammatory pathways, including JAK3 mutations, indicating a different biological background compared to conventional urothelial bladder cancer.
AIMS: Nested variant of urothelial carcinoma (NVUC) is rare, and only a few small series exist. Molecular characteristics and the classifying marker profile as well as therapeutic targets of this specific variant are mostly unknown. The aim of this study was to characterise NVUC at the molecular level in one of the largest cohorts to date. In addition, we applied an immunohistochemical marker panel in order to define the molecular subtype. METHODS AND RESULTS: Sixty NVUC cases were collected from different departments. TERT promoter mutation analysis was carried out in all samples using SNaPshot analysis. Targeted sequencing of 48 cancer-related genes by next-generation sequencing (NGS) analysis was performed in a subset of 26 cases. Immunohistochemical markers CD44, CK5, CK14, EGFR, p63, FOXA1, GATA3, CD24 and CK20 were used to elucidate the molecular subtype. A total of 62.5% of NVUC cases harboured a mutation of the TERT promoter. Additionally, TP53, JAK3 and CTNNB1 were among the most frequently mutated genes identified by NGS analysis. Subtyping revealed that all NVUC express luminal markers such as CD24, FOXA1, GATA3 and CK20. CONCLUSIONS: In summary, NVUC belong to the luminal molecular subtype. Moreover, a subset of NVUC seems to be characterised by mutations of the Wnt and inflammatory pathways, including JAK3 mutations, indicating a different biological background compared to conventional urothelial bladder cancer.
Authors: Francesca Sanguedolce; Magda Zanelli; Andrea Palicelli; Stefano Ascani; Maurizio Zizzo; Giorgia Cocco; Lars Björnebo; Anna Lantz; Ugo Giovanni Falagario; Luigi Cormio; Giuseppe Carrieri Journal: Int J Mol Sci Date: 2022-07-15 Impact factor: 6.208