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

2016-09Journal article Restricted access
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dc.contributor.authorCastelo-Branco, Pedro
dc.contributor.authorLeao, Ricardo
dc.contributor.authorLipman, Tatiana
dc.contributor.authorCampbell, Brittany
dc.contributor.authorLee, Donghyun
dc.contributor.authorPrice, Aryeh
dc.contributor.authorZhang, Cindy
dc.contributor.authorHeidari, Abolfazl
dc.contributor.authorStephens, Derek
dc.contributor.authorBoerno, Stefan
dc.contributor.authorCoelho, Hugo
dc.contributor.authorDomingos, Célia
dc.contributor.authorApolónio, Joana
dc.contributor.authorSchaefer, Georg
dc.contributor.authorBristow, Robert G.
dc.contributor.authorSchweiger, Michal R.
dc.contributor.authorHamilton, Robert
dc.contributor.authorZlotta, Alexandre
dc.contributor.authorFigueiredo, Arnaldo
dc.contributor.authorKlocker, Helmut
dc.contributor.authorSueltmann, Holger
dc.contributor.authorTabori, Uri
dc.date.accessioned2017-04-07T15:56:02Z
dc.date.available2017-04-07T15:56:02Z
dc.date.issued2016-09
dc.description.abstractThe 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).
dc.identifier.doi10.18632/oncotarget.10639
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/10400.1/9293
dc.language.isoeng
dc.peerreviewedyes
dc.publisherImpact Journals
dc.relation.isbasedonWOS:000387153200021
dc.titleA cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort study
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage57736
oaire.citation.issue36
oaire.citation.startPage57726
oaire.citation.titleOncotarget
oaire.citation.volume7
person.familyNameCastelo-Branco
person.familyNameDomingos
person.familyNameApolónio
person.givenNamePedro
person.givenNameCélia
person.givenNameJoana
person.identifier.ciencia-idE015-7F8F-5CA1
person.identifier.ciencia-idC410-E105-17DF
person.identifier.ciencia-id791E-9E39-2795
person.identifier.orcid0000-0002-3453-3978
person.identifier.orcid0000-0002-8828-1366
person.identifier.orcid0000-0002-9727-1813
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublicationbb25b5ad-1769-42be-a7d3-8fe76215aa23
relation.isAuthorOfPublicationc3f4f663-5714-4d31-8fff-41a5ff66ae75
relation.isAuthorOfPublication01cf2be1-ea9f-4082-bcc6-e50fe4ad9fe1
relation.isAuthorOfPublication.latestForDiscovery01cf2be1-ea9f-4082-bcc6-e50fe4ad9fe1

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