title: TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes.
abstract: One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313, Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Vinagre
authors.affiliation: Instituto Gulbenkian de Ciência (IGC), Oeiras, 2780-156, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Nabais
authors.affiliation: Departmento de Patologia, Centro Hospitalar de S. João, Porto, 4200-319, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Pinheiro
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Batista
authors.affiliation: Departmento de Patologia, Centro Hospitalar de Coimbra, Coimbra, 3041-801, Portugal.
authors.forename: Rui Caetano
authors.initials: RC
authors.lastname: Oliveira
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: António Pedro
authors.initials: AP
authors.lastname: Gonçalves
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Pestana
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Reis
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Mesquita
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Vasco
authors.initials: V
authors.lastname: Pinto
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Lyra
authors.affiliation: Departmento de Patologia, Centro Hospitalar de Coimbra, Coimbra, 3041-801, Portugal.
authors.forename: Maria Augusta
authors.initials: MA
authors.lastname: Cipriano
authors.affiliation: Instituto Gulbenkian de Ciência (IGC), Oeiras, 2780-156, Portugal.
authors.forename: Miguel Godinho
authors.initials: MG
authors.lastname: Ferreira
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Departmento de Patologia, Centro Hospitalar de S. João, Porto, 4200-319, Portugal.|Faculdade de Medicina da Universidade do Porto, Porto, 4200-139, Portugal.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Departmento de Patologia, Centro Hospitalar de S. João, Porto, 4200-319, Portugal.|Faculdade de Medicina da Universidade do Porto, Porto, 4200-139, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sobrinho-Simões
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.|Faculdade de Medicina da Universidade do Porto, Porto, 4200-139, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013577:Syndrome; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000201:enzymology / Q000235:genetics; D059505:Telomere Homeostasis / Q000235:genetics; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase