Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer

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

doi:10.1002/ijc.31935

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer

Int J Cancer. 2019 Apr 1;144(7):1676-1684. doi: 10.1002/ijc.31935. Epub 2018 Dec 30.

Authors

Ricardo Leão^{1

2

3

4}, Donghyun Lee², Arnaldo Figueiredo^{3

4}, Thomas Hermanns⁵, Peter Wild⁶, Martin Komosa², Irene Lau², Mathew Mistry², Nuno Miguel Nunes², Aryeh J Price⁷, Cindy Zhang², Tatiana Lipman², Cédric Poyet⁵, Nadejda Valtcheva⁶, Kathrin Oehl⁶, Hugo Coelho⁴, Rashid Sayyid¹, Ana Melo Gomes⁸, Ligia Prado E Castro⁸, Joan Sweet⁹, João Vinagre¹⁰, Joana Apolónio^{11

12

13}, Derek Stephens¹⁴, Inês Faleiro^{11

12

13}, Kamel Fadaak^{1

15}, Patrick O Richard^{1

16}, Girish Kulkarni¹, Alexandre R Zlotta¹, Robert J Hamilton¹, Pedro Castelo-Branco^{11

12

13}, Uri Tabori²

Affiliations

¹ Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada.
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.
⁴ Department of Urology, Coimbra University Hospital, Coimbra, Portugal.
⁵ Department of Urology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
⁶ Institute of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
⁷ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA.
⁸ Department of Pathology, Coimbra University Hospital, Coimbra, Portugal.
⁹ Department of Pathology, University Health Network, Toronto, ON, Canada.
¹⁰ Institute for Research and Innovation in Health, (I3S), Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal.
¹¹ Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
¹² Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
¹³ Algarve Biomedical Center, Faro, Portugal.
¹⁴ Biostatistics, Design and Analysis, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
¹⁶ Division of Urology, Faculty of Medicine, CHUS, University of Sherbrooke, Sherbrooke, QC, Canada.

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 (TERTp^Mut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTp^Mut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTp^Mut 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). TERTp^Mut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THOR^high /TERTp^Mut 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 TERTp^wt and TERTp^Mut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTp^Mut 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: TERT promoter methylation; TERT promoter mutations; progression; recurrence; telomerase; urothelial bladder cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation*
Disease Progression
Epigenesis, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Male
Mutation*
Prognosis
Promoter Regions, Genetic
Sequence Analysis, RNA
Telomerase / genetics*
Up-Regulation
Urinary Bladder Neoplasms / genetics*

Substances

TERT protein, human
Telomerase

Grants and funding

MOP 137899/CIHR/Canada