Yves Allory1, Willemien Beukers2, Ana Sagrera3, Marta Flández3, Miriam Marqués3, Mirari Márquez4, Kirstin A van der Keur2, Lars Dyrskjot5, Irene Lurkin2, Marcel Vermeij2, Alfredo Carrato6, Josep Lloreta7, José A Lorente8, Enrique Carrillo-de Santa Pau3, Roy G Masius2, Manolis Kogevinas9, Ewout W Steyerberg10, Angela A G van Tilborg2, Cheno Abas11, Torben F Orntoft5, Tahlita C M Zuiverloon2, Núria Malats4, Ellen C Zwarthoff2, Francisco X Real12. 1. Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain; Université Paris-Est Créteil, Institut Mondor de Recherche Biomédicale, Créteil, France. 2. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands. 3. Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain. 4. Genetic and Molecular Epidemiology Group, Human Cancer Genetics Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain. 5. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. 6. Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain. 7. Department of Pathology, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. 8. Urology Service, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. 9. Centre de Recerca d'Epidemiologia Ambiental, Barcelona, Spain; IMIM-Institut de Recerca Hospital del Mar, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; National School of Public Health, Athens, Greece. 10. Department of Public Health, Erasmus MC, Rotterdam, The Netherlands. 11. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands; Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain. 12. Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: preal@cnio.es.
Abstract
BACKGROUND: Hotspot mutations in the promoter of the gene coding for telomerase reverse transcriptase (TERT) have been described and proposed to activate gene expression. OBJECTIVES: To investigate TERT mutation frequency, spectrum, association with expression and clinical outcome, and potential for detection of recurrences in urine in patients with urothelial bladder cancer (UBC). DESIGN, SETTING, AND PARTICIPANTS: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription-quantitative polymerase chain reaction. The two most frequent mutations were investigated, using a SNaPshot assay, in an independent set of 184 non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo and 21 mo, respectively). Voided urine from patients with suspicion of incident UBC (n=174), or under surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease-specific survival, and overall survival. RESULTS AND LIMITATIONS: In the two series, 78 of 111 (70%) and 283 of 357 (79%) tumors harbored TERT mutations, C228T being the most frequent substitution (83% for both series). TERT mutations were not associated with clinical or pathologic parameters, but were more frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC patients. The sensitivity was 62% in incident and 42% in recurrent UBC. A limitation of the study is its retrospective nature. CONCLUSIONS: Somatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences.
BACKGROUND: Hotspot mutations in the promoter of the gene coding for telomerase reverse transcriptase (TERT) have been described and proposed to activate gene expression. OBJECTIVES: To investigate TERT mutation frequency, spectrum, association with expression and clinical outcome, and potential for detection of recurrences in urine in patients with urothelial bladder cancer (UBC). DESIGN, SETTING, AND PARTICIPANTS: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription-quantitative polymerase chain reaction. The two most frequent mutations were investigated, using a SNaPshot assay, in an independent set of 184 non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo and 21 mo, respectively). Voided urine from patients with suspicion of incident UBC (n=174), or under surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease-specific survival, and overall survival. RESULTS AND LIMITATIONS: In the two series, 78 of 111 (70%) and 283 of 357 (79%) tumors harbored TERT mutations, C228T being the most frequent substitution (83% for both series). TERT mutations were not associated with clinical or pathologic parameters, but were more frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBCpatients. The sensitivity was 62% in incident and 42% in recurrent UBC. A limitation of the study is its retrospective nature. CONCLUSIONS: Somatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences.
Authors: Sumit Borah; Linghe Xi; Arthur J Zaug; Natasha M Powell; Garrett M Dancik; Scott B Cohen; James C Costello; Dan Theodorescu; Thomas R Cech Journal: Science Date: 2015-02-05 Impact factor: 47.728
Authors: Doreen N Palsgrove; Diana Taheri; Simeon U Springer; Morgan Cowan; Gunes Guner; Maria A Mendoza Rodriguez; Maria Del Carmen Rodriguez Pena; Yuxuan Wang; Isaac Kinde; Bernardo F P Ricardo; Isabela Cunha; Kazutoshi Fujita; Dilek Ertoy; Kenneth W Kinzler; Trinity J Bivalacqua; Nickolas Papadopoulos; Bert Vogelstein; George J Netto Journal: Hum Pathol Date: 2018-11-14 Impact factor: 3.466
Authors: N Ortiz-Brüchle; M Muders; M Toma; I Esposito; A Hartmann; R Stöhr; H Reis; P Wild; J Köllermann; F Bremmer; J Leichsenring; A Stenzinger; S Merkelbach-Bruse; S Kirfel; S Perner; N Hartmann; W Roth; A Jung; T Kirchner; K Schwamborn; N Pfarr; E Dahl; R Knüchel; N T Gaisa Journal: Urologe A Date: 2020-03 Impact factor: 0.639