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00925njm 22002777a 4500 dc López-Jiménez, Elena author Gómez-López, Gonzalo author Leandro-García, L Javier author Muñoz, Iván author Schiavi, Francesca author Montero-Conde, Cristina author de Cubas, Aguirre A author Ramires, Ricardo author Landa, Iñigo author Leskelä, Susanna author Maliszewska, Agnieszka author Inglada-Pérez, Lucía author de la Vega, Leticia author Rodríguez-Antona, Cristina author Letón, Rocío author Bernal, Carmen author de Campos, José M author Diez-Tascón, Cristina author Fraga, Mario F author Boullosa, Cesar author Pisano, David G author Opocher, Giuseppe author Robledo Batanero, Mercedes author Cascon Soriano, Alberto author 2010-12 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. Mol Endocrinol . 2010 Dec;24(12):2382-91. Molecular Endocrinology 20980436 https://hdl.handle.net/20.500.12105/26013 VON-HIPPEL-LINDAU RENAL-CELL CARCINOMA INDUCIBLE FACTOR-I TUMOR-SUPPRESSOR EXPRESSION PROFILES GERMLINE MUTATIONS MICROARRAY DATA HYPOXIA GENE PARAGANGLIOMA Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas.