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Title: TERT structural rearrangements in metastatic pheochromocytomas.
Austin Authors: Dwight, Trisha;Flynn, Aidan;Amarasinghe, Kaushalya;Benn, Diana E;Lupat, Richard;Li, Jason;Cameron, Daniel L;Hogg, Annette;Balachander, Shiva;Candiloro, Ida L M;Wong, Stephen Q;Robinson, Bruce G;Papenfuss, Anthony T;Gill, Anthony J;Dobrovic, Alexander ;Hicks, Rodney J;Clifton-Bligh, Roderick J;Tothill, Richard W
Affiliation: The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
The University of Sydney, Sydney, New South Wales, Australia
The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
The Sir Peter MacCallum Department of OncologyThe University of Melbourne, Parkville, Victoria, Australia
The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
Cancer Diagnosis and Pathology Group, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
Issue Date: Jan-2018 2017-10-03
Publication information: Endocrine-related cancer 2018; 25(1): 1-9
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.
DOI: 10.1530/ERC-17-0306
ORCID: 0000-0003-3414-112X
Journal: Endocrine-related cancer
PubMed URL: 28974544
Type: Journal Article
Subjects: TERT
whole genome sequencing
Appears in Collections:Journal articles

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