Objective: One of the hallmarks of cancer is its unlimited replicative potential. Recently, telomerase promoter (TERTp) mutations were presented as novel mechanism for telomerase re-activation/expression. Due to this fact, it was our objective to study pancreatic endocrine tumours (PET) and related cell lines, to determine if TERTp mutations were present.
Design: We performed characterization of the TERTp in a series of 55 PETs and three common PET cell lines. TERTp mutations were evaluated if they could represent an alternative mechanism in PETs. Additionally, we tested functionally the mutations in vitro, and performed chromatin immunoprecipitation to determine what were the fundamental transcription factors acting on the novel binding sites generated by the mutations.
Results: TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, these mutations confer a two to fourfold increase in telomerase transcription activity. They are able to recruit ETS transcription factor members, in particular GABP-α and ETV1. The findings obtained in tumours are also recapitulated in the cell lines, where TERTp mutated cell line does not rely on alternative lengthening of telomeres mechanism.
Conclusions: We report for the first time TERTp mutations in PETs and derived cell lines. In our series, the mutations were noticeably prevalence in cases with a hereditary component. The data we present point these mutations as an alternative mechanism and in an exclusive manner. In vitro, these alterations are functional and perform in the same manner as presented in other cancer models.
17 - 19 Feb 2016
European Society of Endocrinology