Associação Portuguesa de Investigação em Cancro
Hypermethylation of the TERT promoter predicts biochemical recurrence in prostate cancer: a retrospective study
Hypermethylation of the TERT promoter predicts biochemical recurrence in prostate cancer: a retrospective study
Prostate cancer (PC) is the most common cancer in the male population with a high prevalence from 60 years old. Despite the high prevalence, mortality rates are variable and reflect the heterogeneous nature (clinical and biological) of this disease. Recent studies have shown that most patients with low-risk disease do not need treatment. However, in this apparently homogeneous group, there are patients who have aggressive disease - and benefit from therapy. This highlights the urgent clinical need to find biomarkers that could identify and differentiate in this group, patients with indolent disease and patients with aggressive disease and, thereby adapt the treatment while minimizing their side effects. Recently, our group found a biomarker with prognostic and diagnostic capacity in some cancers. This marker is called THOR and represents a region of the telomerase, which is responsible for cell renewal. In this study we evaluated the role of THOR as a biomarker in CP. THOR shown diagnostic capacity (differentiating benign tissue from malignant) and is associated with disease aggressiveness. The most important fact is that THOR is able to distinguish between the group of patients with low-risk disease, patients in whom the disease progresses and others in which the disease is indolent. The ability to identify these individuals have extraordinary clinical impact and could change the treatment paradigm of patients with low-risk CP.
Authors and Affiliations:
Pedro Castelo-Branco1,2,3, Ricardo Leão1,4,5, Tatiana Lipman1, Brittany Campbell1, Donghyun Lee1, Aryeh Price1, Cindy Zhang1, Abolfazl Heidari1, Derek Stephens1, Stefan Boerno6, Hugo Coelho5, Ana Gomes5, Célia Domingos2,3, Joana D Apolónio2,3, Georg Schäfer11, Robert G Bristow7, Michal R Schweiger8,9 Robert Hamilton4, Alexandre Zlotta10, Arnaldo Figueiredo5, Helmut Klocke11, Holger Sültmann12, Uri Tabori1
1 Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
2 Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
3 Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal
4 Division of Urology, Department of Surgical Oncology Princess Margaret Cancer Center, University of Toronto, Toronto, Canada
5 Serviço de Urologia e Transplantação Renal, Centro Hospitalar Universitário Coimbra EPE, Portugal, Faculty of Medicine, University of Coimbra, Portugal
6 Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany
7 Department of Radiation Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada
8 Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
9 Cologne Center for Genomics, Cologne University
10 Division of Urology, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada, Princess Margaret Cancer Center, Toronto, Ontario, Canada
11 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
12 Cancer Genome Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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).
Journal: Oncotarget
