Oral Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

Structural rearrangements involving the TERT promoter region identified in metastatic pheochromocytomas (#34)

Trish Dwight 1 , Aidan Flynn 2 , Kaushalya Amarasinghe 3 , Diana E Benn 1 , Richard Lupat 3 , Jason Li 3 , Daniel Cameron 3 , Annette Hogg 3 , Shiva Balachander 3 , Stephen Wong 3 , Bruce G Robinson 1 , Sean Grimmond 4 , Tony Papenfuss 3 , Anthony J Gill 5 , Alexander Dobrovich 6 , Rodney J Hicks 7 , Roderick J Clifton-Bligh 1 , Richard W Tothill 7
  1. Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney
  2. The Peter MacCallum Cancer Centre; and Department of Pathology, University of Melbourne, Melbourne
  3. The Peter MacCallum Cancer Centre, Melbourne
  4. The University of Melbourne, Melbourne
  5. Department of Anatomical Pathology and Northern Cancer Translational Research Unit, Royal North Shore Hospital and University of Sydney, Sydney
  6. Olivia Newton-John Cancer Research Institute, Melbourne
  7. The Peter MacCallum Cancer Centre; and The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne

Pheochromocytomas and paragangliomas are neuroendocrine tumours for which the genetic drivers of metastatic progression remain largely unknown.  As a result, the metastatic potential of a tumour can currently only be diagnosed by the presence of metastases.  The early diagnosis of individuals at high risk of developing metastases is therefore clinically important, while the identification of any new biomarkers that are predictive of metastatic potential would be extremely valuable.  Activation of TERT has been associated with a number of malignant tumours, including pheochromocytomas and paragangliomas.  However, the mechanism of TERT activation in the majority of pheochromocytomas and paragangliomas remains unclear.  As TERT promoter mutations occur rarely in these tumours, we hypothesised that other mechanisms - such as structural variations - may underlie TERT activation in these tumours.  We observed moderate to high TERT expression in three of 39 tumours (35 pheochromocytomas, 4 paragangliomas), each of which were pheochromocytomas from individuals with metastatic disease and all of which lacked TERT promoter mutations.  Using whole genome sequencing we identified, for the first time in this disease, somatic structural variants involving the proximal region of the TERT locus in two tumours.  In both of these tumours, the structural variations led to positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for activation of the normally tightly repressed TERT gene.