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

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.

SUBMITTER: Leao R

PROVIDER: S-EPMC6519346 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Leão Ricardo R Lee Donghyun D Figueiredo Arnaldo A Hermanns Thomas T Wild Peter P Komosa Martin M Lau Irene I Mistry Mathew M Nunes Nuno Miguel NM Price Aryeh J AJ Zhang Cindy C Lipman Tatiana T Poyet Cédric C Valtcheva Nadejda N Oehl Kathrin K Coelho Hugo H Sayyid Rashid R Gomes Ana Melo AM Prado E Castro Ligia L Sweet Joan J Vinagre João J Apolónio Joana J Stephens Derek D Faleiro Inês I Fadaak Kamel K Richard Patrick O PO Kulkarni Girish G Zlotta Alexandre R AR Hamilton Robert J RJ Castelo-Branco Pedro P Tabori Uri U

International journal of cancer 20181230 7

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<sup>Mut</sup> ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTp<sup>Mut</sup> and the TERT Hypermethylated Oncological Region (TH ...[more]

PMID: 30350309

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Project description:Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (-57, -124 or -146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.

Dataset Information

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

Publications

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

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