Sara Monteiro-Reis1, Luís Leça2, Mafalda Almeida1, Luís Antunes3, Paula Monteiro2, Paula C Dias2, António Morais4, Jorge Oliveira4, Rui Henrique5, Carmen Jerónimo6. 1. Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal. 2. Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal. 3. Department of Epidemiology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal. 4. Department of Urology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal. 5. Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal. 6. Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal. Electronic address: carmenjeronimo@ipoporto.min-saude.pt.
Abstract
AIM OF THE STUDY: Upper tract urothelial carcinoma (UTUC) accounts for 5-10% of all urothelial tumours. It is mostly diagnosed at advanced stages, entailing a worse prognosis, owing to the lack of early and specific symptoms as well as of effective diagnostic tools. We previously identified a panel of epigenetic biomarkers (GDF15, TMEFF2 and VIM promoter methylation) that accurately identifies bladder cancer in urine. Herein, we assessed the performance of the same panel for UTUC detection and prognosis, in tissue and urine. MATERIAL AND METHODS: Methylation levels of reference and target genes were determined using real-time quantitative methylation-specific polymerase chain reaction (MSP) in bisulphite-modified DNA of 57 UTUC tissues, 36 normal upper tract urothelium (NUTUs), 22 urines from UTUC suspects and 20 urines from controls. Receiver operator characteristics (ROC)-curve analysis was performed to determine the performance of the biomarker panel and survival analyses were conducted to evaluate their prognostic value. RESULTS: Methylation levels of GDF15, TMEFF2 and VIM were significantly higher in UTUC compared to NUTUs (P=0.022; P<0.001; P<0.001, respectively). The panel accurately identified UTUC with 100% and 91% sensitivity, corresponding to an area under the curve of 1.000 and 0.923 in tissue and urines, respectively, with 100% specificity. Low VIM promoter methylation levels independently predicted poor disease-specific survival. CONCLUSIONS: GDF15, TMEFF2 and VIM promoter methylation allows for accurate identification of UTUC, in tissue and urine and VIM methylation provides relevant prognostic information, especially in high-stage disease. This assay may improve the clinical management of UTUC patients.
AIM OF THE STUDY: Upper tract urothelial carcinoma (UTUC) accounts for 5-10% of all urothelial tumours. It is mostly diagnosed at advanced stages, entailing a worse prognosis, owing to the lack of early and specific symptoms as well as of effective diagnostic tools. We previously identified a panel of epigenetic biomarkers (GDF15, TMEFF2 and VIM promoter methylation) that accurately identifies bladder cancer in urine. Herein, we assessed the performance of the same panel for UTUC detection and prognosis, in tissue and urine. MATERIAL AND METHODS: Methylation levels of reference and target genes were determined using real-time quantitative methylation-specific polymerase chain reaction (MSP) in bisulphite-modified DNA of 57 UTUC tissues, 36 normal upper tract urothelium (NUTUs), 22 urines from UTUC suspects and 20 urines from controls. Receiver operator characteristics (ROC)-curve analysis was performed to determine the performance of the biomarker panel and survival analyses were conducted to evaluate their prognostic value. RESULTS: Methylation levels of GDF15, TMEFF2 and VIM were significantly higher in UTUC compared to NUTUs (P=0.022; P<0.001; P<0.001, respectively). The panel accurately identified UTUC with 100% and 91% sensitivity, corresponding to an area under the curve of 1.000 and 0.923 in tissue and urines, respectively, with 100% specificity. Low VIM promoter methylation levels independently predicted poor disease-specific survival. CONCLUSIONS:GDF15, TMEFF2 and VIM promoter methylation allows for accurate identification of UTUC, in tissue and urine and VIM methylation provides relevant prognostic information, especially in high-stage disease. This assay may improve the clinical management of UTUC patients.
Authors: Ekaterina Olkhov-Mitsel; Andrea J Savio; Ken J Kron; Vaijayanti V Pethe; Thomas Hermanns; Neil E Fleshner; Bas W van Rhijn; Theodorus H van der Kwast; Alexandre R Zlotta; Bharati Bapat Journal: Transl Oncol Date: 2017-02-03 Impact factor: 4.243
Authors: Nuno André Padrão; Sara Monteiro-Reis; Jorge Torres-Ferreira; Luís Antunes; Luís Leça; Diana Montezuma; João Ramalho-Carvalho; Paula C Dias; Paula Monteiro; Jorge Oliveira; Rui Henrique; Carmen Jerónimo Journal: Br J Cancer Date: 2017-01-12 Impact factor: 7.640
Authors: Ruth Exner; Walter Pulverer; Martina Diem; Lisa Spaller; Laura Woltering; Martin Schreiber; Brigitte Wolf; Markus Sonntagbauer; Fabian Schröder; Judith Stift; Fritz Wrba; Michael Bergmann; Andreas Weinhäusel; Gerda Egger Journal: Br J Cancer Date: 2015-09-03 Impact factor: 7.640