title: Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma.
abstract: Germline mutations in the RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, NF1 or VHL genes are identified in about 30% of patients with pheochromocytoma or paraganglioma and somatic mutations in RET, VHL or MAX genes are reported in 17% of sporadic tumors. In the present study, using mutation screening of the NF1 gene, mapping of chromosome aberrations by single nucleotide polymorphism (SNP) array, microarray-based expression profiling and immunohistochemistry (IHC), we addressed the implication of NF1 somatic alterations in pheochromocytomas and paragangliomas. We studied 53 sporadic tumors, selected because of their classification with RET/NF1/TMEM127-related tumors by genome wide expression studies, as well as a second set of 11 independent tumors selected on their low individual levels of NF1 expression evaluated by microarray. Direct sequencing of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with loss of the wild-type allele in 84% (21/25) of cases. Gene expression signature of NF1-related tumors highlighted the downregulation of NF1 and the major overexpression of SOX9. Among the second set of 11 tumors, two sporadic tumors carried somatic mutations in NF1 as well as in another susceptibility gene. These new findings suggest that NF1 loss of function is a frequent event in the tumorigenesis of sporadic pheochromocytoma and strengthen the new concept of molecular-based targeted therapy for pheochromocytoma or paraganglioma.
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. nelly.burnichon@inserm.fr
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Alexandre
authors.initials: A
authors.lastname: Buffet
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Céline
authors.initials: C
authors.lastname: Loriot
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
authors.forename: Nasséra
authors.initials: N
authors.lastname: Abermil
authors.forename: Laurence
authors.initials: L
authors.lastname: Valeyrie-Allanore
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
mesh_terms: D000483:Alleles; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D056426:Genetic Loci; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D046228:Microarray Analysis / Q000379:methods; D010235:Paraganglioma / Q000235:genetics; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human