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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 SFRH/BD/102232/2014 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). | URI: | https://hdl.handle.net/10316/108733 | ISSN: | 1949-2553 | DOI: | 10.18632/oncotarget.10639 | Rights: | openAccess |
Appears in Collections: | FMUC Medicina - Artigos em Revistas Internacionais |
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