Browsing by Author "Tabori, Uri"
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- 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).
- Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study.Publication . Gui, Chloe; Wang, Justin Z.; Patil, Vikas; Landry, Alexander P.; Castelo-Branco, Pedro; Singh, Olivia; Tabori, Uri; Aldape, Kenneth; Behling, Felix; Barnholtz-Sloan, Jill S.; Horbinski, Craig; Tabatabai, Ghazaleh; Ajisebutu, Andrew; Liu, Jeff; Patel, Zeel; Yakubov, Rebeca; Kaloti, Ramneet; Ellenbogen, Yosef; Wilson, Christopher; Cohen-Gadol, Aaron; Tatagiba, Marcos; Holland, Eric C.; Sloan, Andrew E.; Chotai, Silky; Chambless, Lola B.; Gao, Andrew; Makarenko, Serge; Yip, Stephen; Nassiri, Farshad; Zadeh, GelarehBackground TERT promoter mutation is a rare biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival. Although high TERT expression is characteristic of tumours with TERT promoter mutations, it has also been observed in tumours with wildtype TERT promoters. This study aimed to investigate the prevalence and prognostic association of TERT expression in meningiomas.
- BRAF Mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade gliomaPublication . Mistry, Matthew; Zhukova, Nataliya; Merico, Daniele; Rakopoulos, Patricia; Krishnatry, Rahul; Shago, Mary; Stavropoulos, James; Alon, Noa; Pole, Jason D.; Ray, Peter N.; Navickiene, Vilma; Mangerel, Joshua; Remke, Marc; Buczkowicz, Pawel; Ramaswamy, Vijay; Stucklin, Ana Guerreiro; Li, Martin; Young, Edwin J.; Zhang, Cindy; Castelo-Branco, Pedro; Bakry, Doua; Laughlin, Suzanne; Shlien, Adam; Chan, Jennifer; Ligon, Keith L.; Rutka, James T.; Dirks, Peter B.; Taylor, Michael D.; Greenberg, Mark; Malkin, David; Huang, Annie; Bouffet, Eric; Hawkins, Cynthia E.; Tabori, UriPurpose To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). Patients and Methods We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. Results sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% 15% and 29% +/- 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). Conclusion BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG. (C) 2015 by American Society of Clinical Oncology
- 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.
- Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancerPublication . Lee, Donghyun D.; Komosa, Martin; Sudhaman, Sumedha; Leão, Ricardo; Zhang, Cindy H.; Apolonio, Joana D.; Hermanns, Thomas; Wild, Peter J.; Klocker, Helmut; Nassiri, Farshad; Zadeh, Gelareh; Diplas, Bill H.; Yan, Hai; Gallinger, Steven; Pugh, Trevor J.; Ramaswamy, Vijay; Taylor, Michael D.; Castelo-Branco, Pedro; Nunes, Nuno Miguel; Tabori, UriAberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression 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.
- Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cellsPublication . Barszczyk, Mark; Buczkowicz, Pawel; Castelo-Branco, Pedro; Mack, Stephen C.; Ramaswamy, Vijay; Mangerel, Joshua; Agnihotri, Sameer; Remke, Marc; Golbourn, Brian; Pajovic, Sanja; Elizabeth, Cynthia; Yu, Man; Luu, Betty; Morrison, Andrew; Adamski, Jennifer; Nethery-Brokx, Kathleen; Li, Xiao-Nan; Van Meter, Timothy; Dirks, Peter B.; Rutka, James T.; Taylor, Michael D.; Tabori, Uri; Hawkins, CynthiaPediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.
- Tert expression in meningiomas predicts progression-free survival independent of tert promoter mutationPublication . Gui, Chloe; Wang, Justin; Patil, Vikas; Landry, Alexander; Castelo-Branco, Pedro; Singh, Olivia; Tabori, Uri; Aldape, Kenneth; Behling, Felix; Barnholtz-Sloan, Jill; Horbinski, Craig; Tabatabai, Ghazaleh; Ajisebutu, Andrew; Liu, Jeff; Patel, Zeel; Yakubov, Rebeca; Kaloti, Ramneet; Ellenbogen, Yosef; Wilson, Christopher; Cohen-Gadol, Aaron; Tatagiba, Marcos; Sloan, Andrew; Holland, Eric; Chambless, Lola; Gao, Andrew; Chotai, Silky; Makarenko, Serge; Yip, Stephen; Nassiri, Farshad; Zadeh, GelarehWhile TERT promoter mutation (TPM) has been es¬tablished as a marker of clinically aggressive meningiomas, this alteration is rare and found in less than 5% of all cases. However, a larger subset of meningiomas may exhibit aberrant TERT expression in the absence of TPMs. This study investigated the effect of TERT gene expression on clinical outcome in meningioma patients. METHODS: Clinical and mo¬lecular data were retrospectively collected on 1241 meningiomas, split into a Toronto discovery cohort and a multi-institutional validation co¬hort. Sanger sequencing and bulk RNA sequencing were used to determine TPM status and TERT gene expression. The effect of TERT expression on progression-free survival (PFS) was assessed using Kaplan-Meier and Cox regression analysis. RESULTS: While meningiomas with TPM showed expectedly higher TERT gene expression compared to wildtype (TP-WT) cases (p<0.0001), TERT expression was still detected in 28.7% (157/547) of TP-WT meningiomas. Meningiomas with TERT expression showed sig¬nificantly worse PFS compared to meningiomas without any TERT expres¬sion. In fact, WHO grade 1 meningiomas with TERT expression had PFS outcomes resembling WHO grade 2 meningiomas lacking TERT expression (p=0.59). In turn, WHO grade 2 meningiomas with TERT expression had clinical outcomes similar to WHO grade 3 meningiomas without TERT ex¬pression (p=0.42). Furthermore, the proportion of meningiomas expressing TERT as well as overall TERT expression levels increased with increasing WHO grade. Multivariable analysis showed that TERT expression was sig-nificantly associated with worse PFS even when controlling for other known predictors of clinical outcome including TPM, CDKN2A/B loss, 1p/22q status and WHO grade (HR 1.85 [95% CI 1.33-2.57], p=0.00024). CON¬CLUSION: TERT expression is a novel independent biomarker of outcome for meningiomas identifiable in up to one-third of cases that may be utilized to reclassify tumors to a higher WHO grade.
- The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancerPublication . Faleiro, Inês; Apolónio, Joana; Price, Aryeh J.; De Mello, Ramon Andrade; Roberto, Vânia; Tabori, Uri; Castelo-Branco, PedroAim: We explore the biomarker potential of the TERT hypermethylated oncologic region (THOR) in pancreatic cancer. Materials & methods: We assessed the methylation status of THOR using the cancer genome atlas data on the cohort of pancreatic cancer (n = 193 patients). Results: THOR was significantly hypermethylated in pancreatic tumor tissue when compared with the normal tissue used as control (p < 0.0001). Also, THOR hypermethylation could distinguish early stage I disease from normal tissue and was associated with worse prognosis. Discussion: We found that THOR is hypermethylated in pancreatic tumor tissue when compared with normal tissue and that THOR methylation correlates with TERT expression in tumor samples. Conclusion: Our preliminary findings support the diagnostic and prognostic values of THOR in pancreatic cancer.