TERT structural rearrangements in metastatic pheochromocytomas
- Trisha Dwight1,2⇑,
- Aidan Flynn3,4,
- Kaushalya Amarasinghe5,
- Diana E Benn1,2,
- Richard Lupat5,
- Jason Li5,
- Daniel L Cameron5,6,7,
- Annette Hogg5,
- Shiva Balachander5,
- Ida L M Candiloro8,9,
- Stephen Q Wong5,
- Bruce G Robinson1,2,
- Anthony T Papenfuss5,6,7,10,11,
- Anthony J Gill2,12,
- Alexander Dobrovic8,9,13,
- Rodney J Hicks5,10,
- Roderick J Clifton-Bligh1,2 and
- Richard W Tothill5,9,10⇑
- 1Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
- 2The University of Sydney, Sydney, New South Wales, Australia
- 3The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark
- 4Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark
- 5The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- 6Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- 7Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
- 8Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
- 9The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
- 10The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
- 11The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
- 12Cancer Diagnosis and Pathology Group, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
- 13School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
- Correspondence should be addressed to T Dwight or R Tothill: trisha.dwight{at}sydney.edu.au or rtothill{at}unimelb.edu.au
Abstract
Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms – such as structural variations – may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells
- Received 30 September 2017
- Accepted 3 October 2017
- Made available online as an Accepted Preprint 3 October 2017
- © 2018 Society for Endocrinology
