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

Pedro Castelo‐Branco ,Brittany Campbell,Arnaldo Figueiredo,Holger Sültmann,Ana Gomes,Ricardo Leão,Robert G Bristow,Tatiana Lipman,Michal R Schweiger,Stefan Boerno,Helmut Klocker,Cindy Zhang,Georg Schäfer,Hugo Coelho,Derek Stephens,Uri Tabori,Abolfazl Heidari,Dong-Hyun Lee ,Joana Apolónio ,Alexandre R Zlotta ,A Price ,Robert J Hamilton ,Célia Domingos

doi:10.18632/oncotarget.10639

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).

Highlights

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second most common cause of cancer-related mortality among men [1]
We recently identified a specific area in the Telomerase Reverse Transcriptase (TERT) promoter, termed THOR (TERT Hypermethylated Oncological Region), which is hypermethylated only in cancers expressing TERT and non-hypermethylated in normal tissues and low-grade pediatric tumors, which do not express TERT
In this study we extend our previous observations, which suggest a clinical role for the methylation signature of the TERT promoter in cancer

Summary

Introduction

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second most common cause of cancer-related mortality among men [1]. One sixth of men will be diagnosed with PCa during their lifetime, only one in thirty six will die from this disease [2]. Prostate cancer is a heterogeneous disease with risk that varies according to host and tumor characteristics that have not been fully elucidated [3, 4]. In view of this heterogeneous behaviour, the clinical challenge resides in maximizing patient survival without overtreatment of indolent tumors. This is especially true in low risk tumors (Gleason 6) where many patients will not experience tumor progression or death from disease and some intermediate risk (Gleason 7) where tumour behavior is heterogeneous [2, 4, 5]

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Results

Conclusion