title: A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.
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).
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.|Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Castelo-Branco
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.|Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Leão
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lipman
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Brittany
authors.initials: B
authors.lastname: Campbell
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aryeh
authors.initials: A
authors.lastname: Price
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Heidari
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: Stephens
authors.affiliation: Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boerno
authors.affiliation: Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Coelho
authors.affiliation: Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Gomes
authors.affiliation: Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.|Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
authors.forename: Celia
authors.initials: C
authors.lastname: Domingos
authors.affiliation: Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.|Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
authors.forename: Joana D
authors.initials: JD
authors.lastname: Apolonio
authors.affiliation: Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.affiliation: Department of Radiation Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Cologne Center for Genomics, Cologne University, Cologne, Germany.
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
authors.affiliation: Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Hamilton
authors.affiliation: Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.|Division of Urology, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Zlotta
authors.affiliation: Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Figueiredo
authors.affiliation: Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.affiliation: Cancer Genome Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D012189:Retrospective Studies; D019098:Telomerase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C509186:TERT protein, human; D019098:Telomerase
keywords: Gleason score; TERT; biomarker; diagnostic; prostate cancer