title: Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma.
abstract: Pheochromocytomas and paragangliomas are neuroendocrine tumors that occur in the context of inherited cancer syndromes in ∼30% of cases and are linked to germline mutations in the VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127 genes. Although genome-wide expression studies have revealed some of the mechanisms likely to be involved in pheochromocytoma/paraganglioma tumorigenesis, the complete molecular distinction of all subtypes of hereditary tumors has not been solved and the genetic events involved in the generation of sporadic tumors are unknown. With these purposes in mind, we investigated 202 pheochromocytomas/paragangliomas, including 75 hereditary tumors, using expression profiling, BAC array comparative genomic hybridization and somatic mutation screening. Gene expression signatures defined the hereditary tumors according to their genotype and notably, led to a complete subseparation between SDHx- and VHL-related tumors. In tumor tissues, the systematic characterization of somatic genetic events associated with germline mutations in tumor suppressor genes revealed loss of heterozygosity (LOH) in a majority of cases, but also detected point mutations and copy-neutral LOH. Finally, guided by transcriptome classifications and LOH profiles, somatic mutations in VHL or RET genes were identified in 14% of sporadic pheochromocytomas/paragangliomas. Overall, we found a germline or somatic genetic alteration in 45.5% (92/202) of the tumors in this large series of pheochromocytomas/paragangliomas. Regarding mutated genes, specific molecular pathways involved in tumorigenesis mechanisms are identified. Altogether, these new findings suggest that somatic mutation analysis is likely to yield important clues for personalizing molecular targeted therapies.
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Center, F-75015 Paris, France. nelly.burnichon@inserm.fr
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Laure
authors.initials: L
authors.lastname: Vescovo
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reynies
authors.forename: Annabelle
authors.initials: A
authors.lastname: Venisse
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouanno
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation / Q000235:genetics*; D010236:Paraganglioma, Extra-Adrenal / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*