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A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study

2016; Impact Journals LLC; Volume: 7; Issue: 36 Linguagem: Inglês

10.18632/oncotarget.10639

1949-2553

Pedro Castelo‐Branco, Ricardo Leão, Tatiana Lipman, Brittany Campbell, Dong‐Hyun Lee, Aryeh J. Price, Cindy Zhang, Abolfazl Heidari, Derek Stephens, Stefan Boerno, Hugo Coelho, Ana Gomes, Célia Domingos, Joana Apolónio, Georg Schäfer, Robert G. Bristow, Michal R. Schweiger, Robert J. Hamilton, Alexandre R. Zlotta, Arnaldo Figueiredo, Helmut Klocker, Holger Sültmann, Uri Tabori,

Telomeres, Telomerase, and Senescence

// Pedro Castelo-Branco 1, 2, 3, * , Ricardo Leão 1, 4, 5, * , Tatiana Lipman 1 , Brittany Campbell 1 , Donghyun Lee 1 , Aryeh Price 1 , Cindy Zhang 1 , Abolfazl Heidari 1 , Derek Stephens 1 , Stefan Boerno 6 , Hugo Coelho 5 , Ana Gomes 5 , Celia Domingos 2, 3 , Joana D. Apolonio 2, 3 , Georg Schäfer 11 , Robert G. Bristow 7 , Michal R. Schweiger 8, 9 , Robert Hamilton 4 , Alexandre Zlotta 4, 10 , Arnaldo Figueiredo 5 , Helmut Klocker 11 , Holger Sültmann 12 , Uri Tabori 1 1 Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 2 Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal 3 Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal 4 Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada 5 Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 6 Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany 7 Department of Radiation Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada 8 Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany 9 Cologne Center for Genomics, Cologne University, Cologne, Germany 10 Division of Urology, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada 11 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria 12 Cancer Genome Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany * These authors contributed equally to this work Correspondence to: Uri Tabori, email: uri.tabori@sickkids.ca Pedro Castelo-Branco, email: pjbranco@ualg.pt Keywords: TERT, prostate cancer, biomarker, diagnostic, Gleason score Received: March 31, 2016 Accepted: June 30, 2016 Published: July 16, 2016 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).