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Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer |
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| Authors: | Ricardo Leão Donghyun Lee Arnaldo Figueiredo Thomas Hermanns Peter Wild Martin Komosa Irene Lau Mathew Mistry Nuno Miguel Nunes Aryeh J Price Cindy Zhang Tatiana Lipman Cédric Poyet Nadejda Valtcheva Kathrin Oehl Hugo Coelho Rashid Sayyid Ana Melo Gomes Ligia Prado e Castro Joan Sweet João Vinagre Joana Apolónio Derek Stephens Inês Faleiro Kamel Fadaak Patrick O Richard Girish Kulkarni Alexandre R Zlotta Robert J Hamilton Pedro Castelo-Branco Uri Tabori |
| Institution: | 1. Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada
Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada Faculty of Medicine, University of Coimbra, Coimbra, Portugal Department of Urology, Coimbra University Hospital, Coimbra, Portugal;2. Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada;3. Faculty of Medicine, University of Coimbra, Coimbra, Portugal Department of Urology, Coimbra University Hospital, Coimbra, Portugal;4. Department of Urology, University Hospital Zürich, University of Zürich, Zürich, Switzerland;5. Institute of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland;6. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA;7. Department of Urology, Coimbra University Hospital, Coimbra, Portugal;8. Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada;9. Department of Pathology, Coimbra University Hospital, Coimbra, Portugal;10. Department of Pathology, University Health Network, Toronto, ON, Canada;11. Institute for Research and Innovation in Health, (I3S), Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal;12. Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal Algarve Biomedical Center, Faro, Portugal;13. Biostatistics, Design and Analysis, The Hospital for Sick Children, Toronto, ON, Canada;14. Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia;15. Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada Division of Urology, Faculty of Medicine, CHUS, University of Sherbrooke, Sherbrooke, QC, Canada;16. Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal |
| Abstract: | In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh/TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer. |
| Keywords: | urothelial bladder cancer telomerase TERT promoter methylation TERT promoter mutations recurrence progression |