title: Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia.
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.
authors.affiliation: 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.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Papathomas
authors.affiliation: 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.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.affiliation: 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.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.affiliation: 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.
authors.forename: Edward
authors.initials: E
authors.lastname: Post
authors.affiliation: 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.
authors.forename: Floor A
authors.initials: FA
authors.lastname: Duijkers
authors.affiliation: 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.
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
authors.affiliation: 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.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.affiliation: 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.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.affiliation: 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.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.affiliation: 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.
authors.forename: David F
authors.initials: DF
authors.lastname: Restuccia
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.affiliation: 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.
authors.forename: Gaston J H
authors.initials: GJ
authors.lastname: Franssen
authors.affiliation: 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.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Timmers
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: 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.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: 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.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: 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.
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.affiliation: 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000328:Adult; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*
chemical_list: D019098:Telomerase
keywords: SDH deficiency; TERT promoter mutations; adrenocortical carcinomas; neuroblastomas; paragangliomas; telomerase reverse transcriptase