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Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer
Author(s) -
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,
Coelho Hugo,
Sayyid Rashid,
Gomes Ana Melo,
Prado e Castro Ligia,
Sweet Joan,
Vinagre João,
Apolónio Joana,
Stephens Derek,
Faleiro Inês,
Fadaak Kamel,
Richard Patrick O.,
Kulkarni Girish,
Zlotta Alexandre R.,
Hamilton Robert J.,
CasteloBranco Pedro,
Tabori Uri
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31935
Subject(s) - epigenetics , bladder cancer , affect (linguistics) , biology , cancer , genetics , cancer research , gene , psychology , communication
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.