Browsing by Author "Price, Aryeh J."
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- 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.
- Screening for colorectal cancer leading into a new decade: the “Roaring ‘20s” for epigenetic biomarkers?Publication . Almeida-Lousada, Hélder; Mestre, André; Ramalhete, Sara Maria Ventura; Price, Aryeh J.; De Mello, Ramon Andrade; Marreiros, Ana; Neves, Ricardo Pires das; Castelo-Branco, PedroColorectal cancer (CRC) has an important bearing (top five) on cancer incidence and mortality in the world. The etiology of sporadic CRC is related to the accumulation of genetic and epigenetic alterations that result in the appearance of cancer hallmarks such as abnormal proliferation, evasion of immune destruction, resistance to apoptosis, replicative immortality, and others, contributing to cancer promotion, invasion, and metastasis. It is estimated that, each year, at least four million people are diagnosed with CRC in the world. Depending on CRC staging at diagnosis, many of these patients die, as CRC is in the top four causes of cancer death in the world. New and improved screening tests for CRC are needed to detect the disease at an early stage and adopt patient management strategies to decrease the death toll. The three pillars of CRC screening are endoscopy, radiological imaging, and molecular assays. Endoscopic procedures comprise traditional colonoscopy, and more recently, capsule-based endoscopy. The main imaging modality remains Computed Tomography (CT) of the colon. Molecular approaches continue to grow in the diversity of biomarkers and the sophistication of the technologies deployed to detect them. What started with simple fecal occult blood tests has expanded to an armamentarium, including mutation detection and identification of aberrant epigenetic signatures known to be oncogenic. Biomarker-based screening methods have critical advantages and are likely to eclipse the classical modalities of imaging and endoscopy in the future. For example, imaging methods are costly and require highly specialized medical personnel. In the case of endoscopy, their invasiveness limits compliance from large swaths of the population, especially those with average CRC risk. Beyond mere discomfort and fear, there are legitimate iatrogenic concerns associated with endoscopy. The risks of perforation and infection make endoscopy best suited for a confirmatory role in cases where there are positive results from other diagnostic tests. Biomarker-based screening methods are largely non-invasive and are growing in scope. Epigenetic biomarkers, in particular, can be detected in feces and blood, are less invasive to the average-risk patient, detect early-stage CRC, and have a demonstrably superior patient follow-up. Given the heterogeneity of CRC as it evolves, optimal screening may require a battery of blood and stool tests, where each can leverage different pathways perturbed during carcinogenesis. What follows is a comprehensive, systematic review of the literature pertaining to the screening and diagnostic protocols used in CRC. Relevant articles were retrieved from the PubMed database using keywords including: “Screening”, “Diagnosis”, and “Biomarkers for CRC”. American and European clinical trials in progress were included as well.
- 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.