Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behaviour of bladder cancer
- Creators
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Leão, Ricardo
- Price, Aryeh J.
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.
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.Attached Files
Published - Le-o_et_al-2018-International_Journal_of_Cancer.pdf
Supplemental Material - ijc31935-sup-0001-supinfo.docx
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Additional details
- Eprint ID
- 90445
- Resolver ID
- CaltechAUTHORS:20181029-083710078
- Created
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2018-10-29Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field