Associação Portuguesa de Investigação em Cancro
Hipermetilação do promotor do gene TERT prediz recorrência bioquímica em cancro da próstata: Estudo retrospetivo
Hipermetilação do promotor do gene TERT prediz recorrência bioquímica em cancro da próstata: Estudo retrospetivo
O cancro da próstata (CP) é o cancro mais frequente na população masculina, com elevada prevalência a partir dos 60 anos de idade. Apesar da alta prevalência, as taxas de mortalidade são variáveis e refletem o carácter heterogéneo (clínico e biológico) desta doença. Recentes estudos demonstraram que grande parte dos doentes com doença de baixo risco, não necessitam de tratamento. No entanto, neste grupo aparentemente homogéneo, há doentes que apresentam doença agressiva – e beneficiam de terapêutica. Este facto salienta a imperiosa necessidade clínica de encontrar marcadores que identifiquem e diferenciem, neste grupo, doentes com doença indolente e doentes com doença agressiva e, desta forma, adequar o tratamento, minimizando os seus efeitos secundários. Recentemente, o nosso grupo descobriu um biomarcador com capacidade diagnóstica e prognóstica em alguns cancros. Este marcador foi por nós denominado (THOR) e representa uma região de um gene (Telomerase) responsável pela renovação celular, a qual é crucial para o desenvolvimento de cancro. Neste trabalho avaliámos o papel de THOR como biomarcador no CP. THOR demonstrou capacidade diagnóstica (diferenciando tecido benigno de maligno) e está relacionado com a agressividade da doença. O facto mais relevante deste estudo reside no facto de THOR ser capaz de distinguir entre o grupo de doentes com doença de baixo risco, doentes em que a doença progride e outros em que a doença é indolente. A capacidade de identificar estes indivíduos tem extraordinário impacto clínico e poderá mudar o paradigma do tratamento de doentes com CP de baixo risco.
Autores e Afiliações:
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).
Revista: Oncotarget
