TERT structural rearrangements in metastatic pheochromocytomas

Trisha Dwight; Aidan Flynn; Kaushalya Amarasinghe; Diana E. Benn; Richard Lupat; Jason Li; Daniel L. Cameron; Annette Hogg; Shiva Balachander; Ida L.M. Candiloro; Stephen Q. Wong; Bruce G. Robinson; Anthony T. Papenfuss; Anthony J. Gill; Alexander Dobrovic; Rodney J. Hicks; Roderick J. Clifton-Bligh; Richard W. Tothill

doi:10.1530/erc-17-0306

TERT structural rearrangements in metastatic pheochromocytomas

Trisha Dwight^*, Aidan Flynn, Kaushalya Amarasinghe, Diana E. Benn, Richard Lupat, Jason Li, Daniel L. Cameron, Annette Hogg, Shiva Balachander, Ida L.M. Candiloro, Stephen Q. Wong, Bruce G. Robinson, Anthony T. Papenfuss, Anthony J. Gill, Alexander Dobrovic, Rodney J. Hicks, Roderick J. Clifton-Bligh, Richard W. Tothill

^*Corresponding author af dette arbejde

23 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Endocrine-Related Cancer
Vol/bind	25
Udgave nummer	1
Sider (fra-til)	1-9
Antal sider	9
ISSN	1351-0088
DOI	https://doi.org/10.1530/erc-17-0306
Status	Udgivet - 2018

Adgang til dokumentet

10.1530/erc-17-0306

ERC-17-0306.pdfForlagets udgivne version, 3,42 MB

Citationsformater

Dwight, T., Flynn, A., Amarasinghe, K., Benn, D. E., Lupat, R., Li, J., Cameron, D. L., Hogg, A., Balachander, S., Candiloro, I. L. M., Wong, S. Q., Robinson, B. G., Papenfuss, A. T., Gill, A. J., Dobrovic, A., Hicks, R. J., Clifton-Bligh, R. J., & Tothill, R. W. (2018). TERT structural rearrangements in metastatic pheochromocytomas. Endocrine-Related Cancer, 25(1), 1-9. https://doi.org/10.1530/erc-17-0306

Dwight, T, Flynn, A, Amarasinghe, K, Benn, DE, Lupat, R, Li, J, Cameron, DL, Hogg, A, Balachander, S, Candiloro, ILM, Wong, SQ, Robinson, BG, Papenfuss, AT, Gill, AJ, Dobrovic, A, Hicks, RJ, Clifton-Bligh, RJ & Tothill, RW 2018, 'TERT structural rearrangements in metastatic pheochromocytomas', Endocrine-Related Cancer, bind 25, nr. 1, s. 1-9. https://doi.org/10.1530/erc-17-0306

@article{f8558aea9a7e45d6b8854756e30f8189,

title = "TERT structural rearrangements in metastatic pheochromocytomas",

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.",

keywords = "Metastatic, Pheochromocytoma, Rearrangements, TERT, Whole genome sequencing",

author = "Trisha Dwight and Aidan Flynn and Kaushalya Amarasinghe and Benn, {Diana E.} and Richard Lupat and Jason Li and Cameron, {Daniel L.} and Annette Hogg and Shiva Balachander and Candiloro, {Ida L.M.} and Wong, {Stephen Q.} and Robinson, {Bruce G.} and Papenfuss, {Anthony T.} and Gill, {Anthony J.} and Alexander Dobrovic and Hicks, {Rodney J.} and Clifton-Bligh, {Roderick J.} and Tothill, {Richard W.}",

year = "2018",

doi = "10.1530/erc-17-0306",

language = "English",

volume = "25",

pages = "1--9",

journal = "Endocrine - Related Cancer",

issn = "1351-0088",

publisher = "BioScientifica Ltd.",

number = "1",

}

TY - JOUR

T1 - TERT structural rearrangements in metastatic pheochromocytomas

AU - Dwight, Trisha

AU - Flynn, Aidan

AU - Amarasinghe, Kaushalya

AU - Benn, Diana E.

AU - Lupat, Richard

AU - Li, Jason

AU - Cameron, Daniel L.

AU - Hogg, Annette

AU - Balachander, Shiva

AU - Candiloro, Ida L.M.

AU - Wong, Stephen Q.

AU - Robinson, Bruce G.

AU - Papenfuss, Anthony T.

AU - Gill, Anthony J.

AU - Dobrovic, Alexander

AU - Hicks, Rodney J.

AU - Clifton-Bligh, Roderick J.

AU - Tothill, Richard W.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Metastatic

KW - Pheochromocytoma

KW - Rearrangements

KW - TERT

KW - Whole genome sequencing

U2 - 10.1530/erc-17-0306

DO - 10.1530/erc-17-0306

M3 - Journal article

C2 - 28974544

AN - SCOPUS:85042535868

SN - 1351-0088

VL - 25

SP - 1

EP - 9

JO - Endocrine - Related Cancer

JF - Endocrine - Related Cancer

IS - 1

ER -

TERT structural rearrangements in metastatic pheochromocytomas

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater