Original articles

Vol. 117: Issue 3 - June 2025

KDM6A expression loss is frequent in low grade non-invasive urothelial carcinomas of the urinary bladder

Authors

Key words: KDM6A deficiency, KDM6A mutation, urothelial carcinoma, immunohistochemistry, tissue microarray
Publication Date: 2025-07-04

Abstract

Objective. The gene lysine demethylase 6A (KDM6A) located on chromosome Xp11 often shows truncating mutations in urothelial carcinoma. Mutations resulting in protein expression loss can be detected by immunohistochemistry (IHC).
Methods. A tissue microarray with >2,500 bladder tumors was analyzed by IHC. 78 cancers were sequenced for KDM6A.
Results. KDM6A expression loss decreased from 36% of 345 pTaG2 low-grade to 23% of 152 pTaG2 high-grade and 18.5% of 92 pTaG3 tumors (p=0.0004) but not further in pT2-4 cancers (17.2-21.9%). KDM6A staining was unrelated to pT, pN, grade, and overall survival (p>0.1894) in 636 patients with pT2-4 cancers. KDM6A loss was more common in male (22.2%) than in female patients (15.4%; p=0.0067), and in tumors from males with Y-chromosome loss (36.1%) than without Y-loss (16.3%; p<0.0001). A KDM6A loss occurred in all 15 male and in 17 (74%) of 23 female patients with a truncating KDM6A mutation, but only 15 (75%) of 20 male and 17 (81%) of 21 female patients with KDM6A expression loss had a truncating mutation.
Conclusions. KDM6A expression loss is frequent in urothelial carcinoma and mostly due to truncating mutations. KDM6A IHC may be a useful tool for the distinction of neoplastic from non-neoplastic urothelial cells in follow-up examinations of patients with KDM6A deficient cancers.

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Authors

Florian Viehweger - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Natalia Gorbokon - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Seyma Büyücek - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Henning Plage - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Sebastian Hofbauer - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Kira Furlano - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Sarah Weinberger - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Bernhard Ralla - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Annika Fendler - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Nadine Biernath - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Barbara Erber - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Florian Roßner - Institute of Pathology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Simon Schallenberg - Institute of Pathology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Sefer Elezkurtaj - Institute of Pathology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Maximilian Lennartz - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Elena Bady - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Claudia Hube-Magg - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Andreas H. Marx - Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany

Henrik Samtleben - Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany

Margit Fisch - Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Michael Rink - Marienhospital Hamburg, Department of Urology, Hamburg, Germany

Henrik Zecha - 2 Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Urology, Albertinen Hospital, Hamburg, Germany

Marcin Slojewski - Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland

Krystian Kaczmarek - Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland;

Thorsten Ecke - Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany

Stefan Koch - Department of Pathology, Helios Hospital Bad Saarow, Bad Saarow, Germany

Nico Adamini - Department of Urology, Albertinen Hospital, Hamburg, Germany

Ronald Simon - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Guido Sauter - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Joachim Weischenfeldt - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Biotech Research & Innovation Center (BRIC), University of Copenhagen, Denmark; Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark

Tobias Klatte - Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany

Thorsten Schlomm - Department of Urology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

David Horst - Institute of Pathology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Martina Kluth - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Sarah Minner - Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

How to Cite
Viehweger, F., Gorbokon, N., Büyücek S., Plage, H., Hofbauer, S., Furlano, K., Weinberger, S., Ralla, B., Fendler, A., Biernath, N., Erber, B., Roßner, F., Schallenberg, S., Elezkurtaj, S., Lennartz, M., Bady, E., Hube-Magg, C. ., Marx, A. H., Samtleben, H., Fisch, M., Rink, M., Zecha, H., Slojewski, M., Kaczmarek, K., Ecke, T., Koch, S., Adamini, N., Simon, R., Sauter, G., Weischenfeldt, J., Klatte, T., Schlomm, T., Horst, D., Kluth, M., & Minner, S. (2025). KDM6A expression loss is frequent in low grade non-invasive urothelial carcinomas of the urinary bladder. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, 117(3). https://doi.org/10.32074/1591-951X-1104
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