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Nat Commun. 2015 Jan 27;6:6044. doi: 10.1038/ncomms7044.

Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas.

Author information

1
1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
2
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 75013 Paris, France.
3
1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [3] Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
4
1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [3] Hypertension Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
5
1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [3] Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
6
1] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [2] Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, F-75006 Paris, France.
7
1] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [2] Department of Digestive and Endocrine Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, F-75006 Paris, France [3] INSERM, U1016, Institut Cochin, F-75006 Paris, France [4] CNRS UMR8104, F-75006 Paris, France.
8
1] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [2] INSERM, U1016, Institut Cochin, F-75006 Paris, France [3] CNRS UMR8104, F-75006 Paris, France [4] Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, F-75006 Paris, France [5] Rare Adrenal Cancer Network COMETE, F-75006 Paris, France.
9
1] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [2] Department of Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
10
1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [3] Hypertension Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France [4] Rare Adrenal Cancer Network COMETE, F-75006 Paris, France.
11
1] INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France [3] Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France [4] Rare Adrenal Cancer Network COMETE, F-75006 Paris, France.

Abstract

Pheochromocytomas and paragangliomas (PCCs/PGLs) are neural crest-derived tumours with a very strong genetic component. Here we report the first integrated genomic examination of a large collection of PCC/PGL. SNP array analysis reveals distinct copy-number patterns associated with genetic background. Whole-exome sequencing shows a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identify DNA methylation changes and miRNA expression clusters strongly associated with messenger RNA expression profiling. Overexpression of the miRNA cluster 182/96/183 is specific in SDHB-mutated tumours and induces malignant traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appears as a potential driver in a subgroup of sporadic tumours. Altogether, the complete genomic landscape of PCC/PGL is mainly driven by distinct germline and/or somatic mutations in susceptibility genes and reveals different molecular entities, characterized by a set of unique genomic alterations.

PMID:
25625332
PMCID:
PMC4354166
DOI:
10.1038/ncomms7044
[Indexed for MEDLINE]
Free PMC Article

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