title: Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas.
abstract: Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. jenny.welander@liu.se
authors.forename: Jenny
authors.initials: J
authors.lastname: Welander
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.forename: Martin
authors.initials: M
authors.lastname: Bäckdahl
authors.forename: Niyaz
authors.initials: N
authors.lastname: Hareni
authors.forename: Tobias
authors.initials: T
authors.lastname: Sivlér
authors.forename: Michael
authors.initials: M
authors.lastname: Brauckhoff
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.forename: Oliver
authors.initials: O
authors.lastname: Gimm
mesh_terms: D000483:Alleles; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016514:Genes, Neurofibromatosis 1; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D046228:Microarray Analysis / Q000379:methods; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger