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Endocr Relat Cancer. 2014 Aug;21(4):653-61. doi: 10.1530/ERC-13-0429. Epub 2014 Jun 20.

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia.

Author information

1
Department of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
2
Department of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The NetherlandsDepartment of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
3
Department of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands e.korpershoek.1@erasmusmc.nl.

Abstract

Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.

KEYWORDS:

SDH deficiency; TERT promoter mutations; adrenocortical carcinomas; neuroblastomas; paragangliomas; telomerase reverse transcriptase

PMID:
24951106
DOI:
10.1530/ERC-13-0429
[Indexed for MEDLINE]

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