title: Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas.
abstract: The six major genes involved in hereditary susceptibility for pheochromocytoma (PCC)/paraganglioma (PGL) (RET, VHL, NF1, SDHB, SDHC, and SDHD) have been recently integrated into the same neuronal apoptotic pathway where mutations in any of these genes lead to cell death. In this model, prolyl hydroxylase 3 (EglN3) abrogation plays a pivotal role, but the molecular mechanisms underlying its inactivation are currently unknown. The aim of the study was to decipher specific alterations associated with the different genetic classes of PCCs/PGLs. With this purpose, 84 genetically characterized tumors were analyzed by means of transcriptional profiling. The analysis revealed a hypoxia-inducible factor (HIF)-related signature common to succinate dehydrogenase (SDH) and von Hippel-Lindau (VHL) tumors, that differentiated them from RET and neurofibromatosis type 1 cases. Both canonical HIF-1α and HIF-2α target genes were overexpressed in the SDH/VHL cluster, suggesting that a global HIF deregulation accounts for this common profile. Nevertheless, when we compared VHL tumors with SDHB cases, which often exhibit a malignant behavior, we found that HIF-1α target genes showed a predominant activation in the VHL PCCs. Expression data from 67 HIF target genes was sufficient to cluster SDHB and VHL tumors into two different groups, demonstrating different pseudo-hypoxic signatures. In addition, VHL-mutated tumors showed an unexpected overexpression of EglN3 mRNA that did not lead to significantly different EglN3 protein levels. These findings pave the way for more specific therapeutic approaches for malignant PCCs/PGLs management based on the patient's genetic alteration.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: López-Jiménez
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.forename: L Javier
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: Iván
authors.initials: I
authors.lastname: Muñoz
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Cristina
authors.initials: C
authors.lastname: Montero-Conde
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ramires
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Susanna
authors.initials: S
authors.lastname: Leskelä
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maliszewska
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Leticia
authors.initials: L
authors.lastname: de la Vega
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Carmen
authors.initials: C
authors.lastname: Bernal
authors.forename: José M
authors.initials: JM
authors.lastname: de Campos
authors.forename: Cristina
authors.initials: C
authors.lastname: Diez-Tascón
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Cesar
authors.initials: C
authors.lastname: Boullosa
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics*; D002648:Child; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049308:Dioxygenases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C488894:EGLN3 protein, human; C108095:SDHB protein, human; C497446:VHL protein, human