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Nat Commun. 2015 Jan 21;6:6140. doi: 10.1038/ncomms7140.

Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
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.
4
Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
5
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.
6
Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
7
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
8
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.
9
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.
10
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.
11
Division of Renal and Hypertension, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
12
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.

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.

PMID:
25608029
PMCID:
PMC4302757
DOI:
10.1038/ncomms7140
[Indexed for MEDLINE]
Free PMC Article

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