title: Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas.
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.
authors.affiliation: 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.
authors.forename: Luis Jaime
authors.initials: LJ
authors.lastname: Castro-Vega
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 75013 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: 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.
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.affiliation: 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.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Buffet
authors.affiliation: 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.
authors.forename: Pierre-Hélie
authors.initials: PH
authors.lastname: Disderot
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Khalifa
authors.affiliation: 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.
authors.forename: Céline
authors.initials: C
authors.lastname: Loriot
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 75013 Paris, France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Elarouci
authors.affiliation: 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.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Morin
authors.affiliation: 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.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Menara
authors.affiliation: 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.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lepoutre-Lussey
authors.affiliation: 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.
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.affiliation: 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.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.affiliation: 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.affiliation: 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.
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.affiliation: 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.
authors.forename: Franck
authors.initials: F
authors.lastname: Zinzindohoue
authors.affiliation: 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.
authors.forename: Pierre François
authors.initials: PF
authors.lastname: Plouin
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 75013 Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.affiliation: 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.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D019175:DNA Methylation / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D035683:MicroRNAs