TERT promoter mutations in pancreatic endocrine tumours

²Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, 4200-465, Portugal.

³Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313, Porto, Portugal.

⁴Instituto Gulbenkian de Ciência (IGC), Oeiras, 2780-156, Portugal.

⁵Departmento de Patologia, Centro Hospitalar de S. João, Porto, 4200-319, Portugal.

⁶Departmento de Patologia, Centro Hospitalar de Coimbra, Coimbra, 3041-801, Portugal.

⁷Faculdade de Medicina da Universidade do Porto, Porto, 4200-139, Portugal.

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.