BACKGROUND: Frequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated. METHODS: To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients. RESULTS: We show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer. CONCLUSIONS: We identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis.

CBmed Center for Biomarker Research in Medicine GmbH 8010 Graz Austria

CEITEC Masaryk University Brno Czech Republic

Central European Institute of Technology Masaryk University Brno 62500 Czech Republic

Christian Doppler Laboratory for Applied Metabolomics 1090 Vienna Austria

Department of Pathology University Cambridge Cambridge UK

Department of Urology Innsbruck Medical University 6020 Innsbruck Austria

Division of Experimental and Translational Pathology Department of Pathology Medical University of Vienna 1090 Vienna Austria

Division of Nuclear Medicine Department of Biomedical Imaging and Image Guided Therapy Medical University of Vienna 1090 Vienna Austria

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna 1210 Vienna Austria

Institute of Biochemistry Christian Albrechts University Kiel 24118 Kiel Germany

Institute of Medical Genetics Medical University of Vienna 1090 Vienna Austria

Institute of Pharmacology and Toxicology University of Veterinary Medicine Vienna 1210 Vienna Austria

Ludwig Boltzmann Institute Applied Diagnostics 1090 Vienna Austria

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna 1210 Vienna Austria

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