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Title: A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study
Authors: Castelo Branco, Pedro 
Leão, Ricardo 
Lipman, Tatiana
Campbell, Brittany
Lee, Donghyun
Price, Aryeh
Zhang, Cindy
Heidari, Abolfazl
Stephens, Derek
Boerno, Stefan
Coelho, Hugo
Gomes, Ana
Domingos, Celia
Apolonio, Joana D
Schäfer, Georg
Bristow, Robert G
Schweiger, Michal R
Hamilton, Robert
Zlotta, Alexandre
Figueiredo, Arnaldo 
Klocker, Helmut
Sültmann, Holger
Tabori, Uri 
Keywords: TERT; prostate cancer; biomarker; diagnostic; Gleason score
Issue Date: 6-Sep-2016
Publisher: Impact Journals
Project: The Canadian Institute of Health Research; 
Canadian Cancer Society Research Institute, 
MaRS Innovation 
UID/BIM/04773/2013 CBMR 1334 
Volkswagenstiftung (Lichtenberg Program) 
Serial title, monograph or event: Oncotarget
Volume: 7
Issue: 36
Abstract: The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73-100) and 65% (95% CI 52-78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).
ISSN: 1949-2553
DOI: 10.18632/oncotarget.10639
Rights: openAccess
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais

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