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

Leão, Ricardo and Price, Aryeh J. (2019) Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behaviour of bladder cancer. International Journal of Cancer, 144 (7). pp. 1676-1684. ISSN 0020-7136. http://resolver.caltech.edu/CaltechAUTHORS:20181029-083710078

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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 TERTHypermethylated 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 non‐muscle 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/ijc.31935DOIArticle
ORCID:
AuthorORCID
Leão, Ricardo0000-0003-3719-717X
Additional Information:© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Accepted manuscript online: 23 October 2018; Manuscript accepted: 26 September 2018; Manuscript revised: 13 September 2018; Manuscript received: 04 May 2018. Ethics approval and consent to participate: Research Ethics Board of each Institution involved approved our study. The authors do not have any conflicts of interest. Any views, opinions, findings and conclusions expressed in our study are those solely of the authors.
Subject Keywords:Urothelial bladder cancer; telomerase; TERT promoter methylation; TERT promoter mutations; recurrence; progression
Record Number:CaltechAUTHORS:20181029-083710078
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181029-083710078
Official Citation:Leão, R. , Lee, D. , Figueiredo, A. , Hermanns, T. , Wild, P. , Komosa, M. , Lau, I. , Mistry, M. , Nunes, N. M., Price, A. J., Zhang, C. , Lipman, T. , Poyet, C. , Valtcheva, N. , Oehl, K. , Coelho, H. , Sayyid, R. , Gomes, A. M., Prado e Castro, L. , Sweet, J. , Vinagre, J. , Apolónio, J. , Stephens, D. , Faleiro, I. , Fadaak, K. , Richard, P. O., Kulkarni, G. , Zlotta, A. R., Hamilton, R. J., Castelo‐Branco, P. and Tabori, U. (2019), Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer. Int. J. Cancer, 144: 1676-1684. doi:10.1002/ijc.31935
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90445
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:29 Oct 2018 15:47
Last Modified:04 Feb 2019 21:26

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