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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.

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