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


Leão, Ricardo; Lee, Donghyun; Figueiredo, Arnaldo; Hermanns, Thomas; Wild, Peter; Komosa, Martin; Lau, Irene; Mistry, Mathew; Nunes, Nuno Miguel; Price, Aryeh J; Zhang, Cindy; Lipman, Tatiana; Poyet, Cédric; Valtcheva, Nadejda; Oehl, Kathrin; et al (2019). Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behaviour of bladder cancer. International Journal of Cancer, 144(7):1676-1684.

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 ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTp 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 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 alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p<0.0001) but not progression in NMIBC. Combined THOR /TERTp 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 and TERTp NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTp 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. This article is protected by copyright. All rights reserved.

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 ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTp 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 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 alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p<0.0001) but not progression in NMIBC. Combined THOR /TERTp 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 and TERTp NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTp 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. This article is protected by copyright. All rights reserved.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 April 2019
Deposited On:23 Nov 2018 08:47
Last Modified:24 Sep 2019 23:52
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0020-7136
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/ijc.31935
PubMed ID:30350309

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