title: Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas.
abstract: Pheochromocytomas and paragangliomas (PCC/PGL) are the solid tumour type most commonly associated with an inherited susceptibility syndrome. However, very little is known about the somatic genetic changes leading to tumorigenesis or malignant transformation. Here we perform whole-exome sequencing on a discovery set of 21 PCC/PGL and identify somatic ATRX mutations in two SDHB-associated tumours. Targeted sequencing of a separate validation set of 103 PCC/PGL identifies somatic ATRX mutations in 12.6% of PCC/PGL. PCC/PGL with somatic ATRX mutations are associated with alternative lengthening of telomeres and clinically aggressive behaviour. This finding suggests that loss of ATRX, an SWI/SNF chromatin remodelling protein, is important in the development of clinically aggressive PCC/PGL.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Fishbein
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sanika
authors.initials: S
authors.lastname: Khare
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.affiliation: 1] Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Center for Personalized Diagnostics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: DeSloover
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shana
authors.initials: S
authors.lastname: Merrill
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Nam Woo
authors.initials: NW
authors.lastname: Cho
authors.affiliation: 1] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Else
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Montone
authors.affiliation: 1] Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: LiVolsi
authors.affiliation: 1] Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Division of Oncologic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Fraker
authors.affiliation: 1] Center for Personalized Diagnostics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Daber
authors.affiliation: Division of Renal and Hypertension, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Cohen
authors.affiliation: 1] Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D059505:Telomere Homeostasis; D000075924:X-linked Nuclear Protein
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein