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

• Autor(a) principal: Castelo Branco, Pedro
• Data de Publicação: 2016
• Outros Autores: 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
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/108733; https://doi.org/10.18632/oncotarget.10639
• topic: TERT; prostate cancer; biomarker; diagnostic; Gleason score; Aged; Biomarkers, Tumor; Cell Differentiation; DNA Methylation; Epigenesis, Genetic; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Proportional Hazards Models; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Telomerase

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).