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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenal Gland Neoplasms / genetics*
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Adrenal Gland Neoplasms / metabolism
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Adrenal Gland Neoplasms / pathology
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Chromatin / chemistry
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Chromatin / metabolism
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Chromatin Assembly and Disassembly
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DNA Helicases / genetics*
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DNA Helicases / metabolism
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Exome*
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Gene Expression
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Genetic Predisposition to Disease
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Head and Neck Neoplasms / genetics*
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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High-Throughput Nucleotide Sequencing
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Humans
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Mutation
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Paraganglioma / genetics*
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Paraganglioma / metabolism
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Paraganglioma / pathology
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Pheochromocytoma / genetics*
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Pheochromocytoma / metabolism
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Pheochromocytoma / pathology
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Succinate Dehydrogenase / genetics
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Succinate Dehydrogenase / metabolism
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Telomere / ultrastructure
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Telomere Homeostasis
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X-linked Nuclear Protein
Substances
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Chromatin
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Nuclear Proteins
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SDHB protein, human
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Succinate Dehydrogenase
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DNA Helicases
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ATRX protein, human
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X-linked Nuclear Protein