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A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.
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.
Afiliación
  • Castelo-Branco P; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Leão R; Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
  • Lipman T; Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
  • Campbell B; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Lee D; Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.
  • Price A; Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
  • Zhang C; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Heidari A; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Stephens D; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Boerno S; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Coelho H; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Gomes A; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Domingos C; Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • Apolonio JD; Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Schäfer G; Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
  • Bristow RG; Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
  • Schweiger MR; Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
  • Hamilton R; Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
  • Zlotta A; Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
  • Figueiredo A; Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.
  • Klocker H; Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
  • Sültmann H; Department of Radiation Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada.
  • Tabori U; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Oncotarget ; 7(36): 57726-57736, 2016 09 06.
Article en En | MEDLINE | ID: mdl-27437772
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Telomerasa Tipo de estudio: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Humans / Male / Middle aged Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Telomerasa Tipo de estudio: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Humans / Male / Middle aged Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos