Browsing by Author "Figueiredo, Arnaldo"
Now showing 1 - 4 of 4
Results Per Page
Sort Options
- A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort studyPublication . Castelo-Branco, Pedro; Leao, Ricardo; Lipman, Tatiana; Campbell, Brittany; Lee, Donghyun; Price, Aryeh; Zhang, Cindy; Heidari, Abolfazl; Stephens, Derek; Boerno, Stefan; Coelho, Hugo; Domingos, Célia; Apolónio, Joana; Schaefer, Georg; Bristow, Robert G.; Schweiger, Michal R.; Hamilton, Robert; Zlotta, Alexandre; Figueiredo, Arnaldo; Klocker, Helmut; Sueltmann, Holger; Tabori, UriThe 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).
- Cancer stem cells in prostate cancer: implications for targeted therapyPublication . Leao, Ricardo; Domingos, Célia; Figueiredo, Arnaldo; Hamilton, Robert; Tabori, Uri; Castelo-Branco, PedroProstate cancer (PCa) is the most frequently diagnosed cancer in men and the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies include surgery, radiation, hormonal ablation, and chemotherapy. Despite increasing efforts, these therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. The cancer stem cell (CSC) hypothesis is an emerging model that explains many of the molecular characteristics of oncological disease as well as the tendency of cancers to relapse, metastasize, and develop resistance to conventional therapies. CSCs are a reservoir of cancer cells that exhibit properties of self-renewal and the ability to reestablish the heterogeneous tumor cell population. The existence of PCa stem cells offers a theoretical explanation for many uncertainties regarding PCa and also for treatment resistance and disease progression once clinical cure is achieved. Therapies targeting CSCs might therefore lead to more effective cancer treatments, divergent from a traditional anti-proliferative approach, based on tumor bulk reduction accompanied by CSC-specific inhibition. Here, we focus on reviewing the historical perspective as well as concepts regarding stem cells and CSCs in PCa. In addition, we will report possible strategies and new clinical approaches that address the CSC-based concept of tumorigenesis in PCa. (C) 2017 S. Karger AG, Basel
- Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancerPublication . Leão, Ricardo; Lee, Donghyun; Figueiredo, Arnaldo; Hermanns, Thomas; Wild, Peter; Komosa, Martin; Lau, Irene; Mistry, Mathew; Nunes, Nuno Miguel; Price, Aryeh J.; Zhang, Cindy; Lipman, Tatiana; Poyet, Cédric; Valtcheva, Nadejda; Oehl, Kathrin; Coelho, Hugo; Sayyid, Rashid; Gomes, Ana Melo; Prado e Castro, Ligia; Sweet, Joan; Vinagre, João; Apolónio, Joana; Stephens, Derek; Faleiro, Inês; Fadaak, Kamel; Richard, Patrick O.; Kulkarni, Girish; Zlotta, Alexandre R.; Hamilton, Robert J.; Castelo-Branco, Pedro; Tabori, UriIn urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh /TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer.
- Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancerPublication . Leão, Ricardo; Apolónio, Joana; Lee, Donghyun; Figueiredo, Arnaldo; Tabori, Uri; Castelo-Branco, PedroBackground Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.