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 ( TERT p Mut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERT p 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 TER Tp 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). TERT p 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 / TER Tp 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 TERT p wt and TERT p Mut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERT p 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.

Complex context relationships between DNA methylation and accessibility, histone marks, and hTERT gene expression in acute promyelocytic leukemia cells: perspectives for all‐trans retinoic acid in cancer therapy

“…Our previous study performed on APL cell lines identified two distinct functional domains in hTERT promoter, one distal and one proximal, differentially methylated (Azouz et al , 2010). These results are in agreement with the recent identification of the TERT hypermethylation oncologic region, a 433‐bp genomic region located −159 to −591 bp upstream the TSS (Castelo‐Branco et al , 2016; Leao et al , 2019; Lee et al , 2019), as a potential biomarker in several cancers. This region is of major importance, because its methylation status correlates with hTERT expression.…”

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study

“…THOR hypermethylation has been found as an alternative telomerase-activating mechanism in cancer that can act independently or in conjunction with TERT promoter mutations, further supporting the utility of THOR hypermethylation as a prognostic biomarker (Lee et al, 2018). Other studies highlight that both THOR hypermethylation and TERT promoter mutations are common and coexist in bladder cancer, and while TERT promoter mutation behaves as an early event in bladder carcinogenesis, THOR hypermethylation seems associated with disease progression, with the combined genetic and epigenetic alterations of TERT bringing additional prognostic value in NMIBC (Leão et al, 2019). TERT promoter mutations per se emerged as a novel biomarker detected in up to 80% of bladder cancer, independently of stage or grade (Rachakonda et al, 2013;Allory et al, 2014;Hurst et al, 2014;Hosen et al, 2015).…”

Biomarkers for Bladder Cancer Diagnosis and Surveillance: A Comprehensive Review

“…THOR is an alternative telomerase-activating mechanism in cancer and can be a prognostic biomarker [78]. Directly related to BC, THOR hypermethylation and TERTp mutations are common and coexist in BC; THOR hypermethylation associates with disease progression, with the combined genetic and epigenetic alterations of TERT, bringing additional prognostic value in NMIBC [79].…”