Oncotarget

Research Papers:

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

Pedro Castelo-Branco, Ricardo Leão, Tatiana Lipman, Brittany Campbell, Donghyun Lee, Aryeh Price, Cindy Zhang, Abolfazl Heidari, Derek Stephens, Stefan Boerno, Hugo Coelho, Ana Gomes, Celia Domingos, Joana D. Apolonio, Georg Schäfer, Robert G. Bristow, Michal R. Schweiger, Robert Hamilton, Alexandre Zlotta, Arnaldo Figueiredo, Helmut Klocker, Holger Sültmann and Uri Tabori _

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Oncotarget. 2016; 7:57726-57736. https://doi.org/10.18632/oncotarget.10639

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Abstract

Pedro Castelo-Branco1,2,3,*, Ricardo Leão1,4,5,*, Tatiana Lipman1, Brittany Campbell1, Donghyun Lee1, Aryeh Price1, Cindy Zhang1, Abolfazl Heidari1, Derek Stephens1, Stefan Boerno6, Hugo Coelho5, Ana Gomes5, Celia Domingos2,3, Joana D. Apolonio2,3, Georg Schäfer11, Robert G. Bristow7, Michal R. Schweiger8,9, Robert Hamilton4, Alexandre Zlotta4,10, Arnaldo Figueiredo5, Helmut Klocker11, Holger Sültmann12, Uri Tabori1

1Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

2Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal

3Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal

4Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada

5Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

6Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany

7Department of Radiation Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada

8Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany

9Cologne Center for Genomics, Cologne University, Cologne, Germany

10Division of Urology, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada

11Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

12Cancer 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: [email protected]

Pedro Castelo-Branco, email: [email protected]

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).


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