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

Luis Jaime Castro-Vega; Eric Letouzé; Nelly Burnichon; Alexandre Buffet; Pierre-Hélie Disderot; Emmanuel Khalifa; Céline Loriot; Nabila Elarouci; Aurélie Morin; Mélanie Menara; Charlotte Lepoutre-Lussey; Cécile Badoual; Mathilde Sibony; Bertrand Dousset; Rossella Libé; Franck Zinzindohoue; Pierre François Plouin; Jérôme Bertherat; Laurence Amar; Aurélien de Reyniès; Judith Favier; Anne-Paule Gimenez-Roqueplo

doi:10.1038/ncomms7044

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

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

Authors

Luis Jaime Castro-Vega¹, Eric Letouzé², Nelly Burnichon³, Alexandre Buffet³, Pierre-Hélie Disderot¹, Emmanuel Khalifa³, Céline Loriot¹, Nabila Elarouci², Aurélie Morin¹, Mélanie Menara¹, Charlotte Lepoutre-Lussey⁴, Cécile Badoual⁵, Mathilde Sibony⁶, Bertrand Dousset⁷, Rossella Libé⁸, Franck Zinzindohoue⁹, Pierre François Plouin¹⁰, Jérôme Bertherat⁸, Laurence Amar⁴, Aurélien de Reyniès², Judith Favier¹, Anne-Paule Gimenez-Roqueplo¹¹

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adrenal Gland Neoplasms / genetics*
Adult
Aged
Aged, 80 and over
Child
Cohort Studies
DNA Copy Number Variations
DNA Methylation / genetics
Exome / genetics
Female
Gene Expression Profiling
Genetic Predisposition to Disease*
Genome, Human / genetics*
Genomics / methods*
Humans
Male
MicroRNAs / genetics
MicroRNAs / metabolism
Middle Aged
Mutation / genetics*
Paraganglioma / genetics*
Pheochromocytoma / genetics*
Sequence Analysis, DNA
Young Adult

Substances

MicroRNAs