Castelo-Branco, Pedro, Leao, Ricardo ORCID: 0000-0003-3719-717X, Lipman, Tatiana, Campbell, Brittany, Lee, Donghyun, Price, Aryeh, Zhang, Cindy, Heidari, Abolfazl, Stephens, Derek, Boerno, Stefan, Coelho, Hugo ORCID: 0000-0002-9867-0373, Gomes, Ana ORCID: 0000-0001-7734-2074, Domingos, Celia ORCID: 0000-0002-8828-1366, Apolonio, Joana D., Schaefer, Georg, Bristow, Robert G., Schweiger, Michal R., Hamilton, Robert, Zlotta, Alexandre, Figueiredo, Arnaldo ORCID: 0000-0002-7157-0081, Klocker, Helmut, Sueltmann, Holger and Tabori, Uri (2016). A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort study. Oncotarget, 7 (36). S. 57726 - 57737. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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).

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Castelo-Branco, PedroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leao, RicardoUNSPECIFIEDorcid.org/0000-0003-3719-717XUNSPECIFIED
Lipman, TatianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, BrittanyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, DonghyunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Price, AryehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, CindyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heidari, AbolfazlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stephens, DerekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boerno, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coelho, HugoUNSPECIFIEDorcid.org/0000-0002-9867-0373UNSPECIFIED
Gomes, AnaUNSPECIFIEDorcid.org/0000-0001-7734-2074UNSPECIFIED
Domingos, CeliaUNSPECIFIEDorcid.org/0000-0002-8828-1366UNSPECIFIED
Apolonio, Joana D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bristow, Robert G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamilton, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zlotta, AlexandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueiredo, ArnaldoUNSPECIFIEDorcid.org/0000-0002-7157-0081UNSPECIFIED
Klocker, HelmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sueltmann, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tabori, UriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-262540
DOI: 10.18632/oncotarget.10639
Journal or Publication Title: Oncotarget
Volume: 7
Number: 36
Page Range: S. 57726 - 57737
Date: 2016
Publisher: IMPACT JOURNALS LLC
Place of Publication: ORCHARD PARK
ISSN: 1949-2553
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CIRCULATING TUMOR-CELLS; RADICAL PROSTATECTOMY; TELOMERASE ACTIVITY; INTRAEPITHELIAL NEOPLASIA; NATURAL-HISTORY; METHYLATION; RECURRENCE; PROGRESSION; HETEROGENEITY; LENGTHMultiple languages
Oncology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26254

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