title: Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas.
abstract: Central nervous system hemangioblastomas (CNS-HBs) occur sporadically or as a component of von Hippel-Lindau-VHL syndrome. CNS-HBs share some molecular similarities with pheochromocytomas/paragangliomas (PPGLs) and renal cell carcinomas (RCCs). Recently, hypoxia-inducible factors, particularly somatic HIF2A mutations, have been found to play an important role in the pathogenesis of PPGLs. Somatic mutations in HIF2A have been reported in PPGLs associated with polycythemia, which have been reported to also be present in patients with RCCs and HBs. However, whether CNS-HBs is associated with the presence of a HIF2A mutation is currently uknown. We analyzed somatic HIF2A and VHL mutations in a series of 28 sporadic CNS-HBs. We also investigated the expression of HIF target proteins and hypoxia-associated factor (HAF). Two sporadic CNS-HBs were found to have somatic HIF2A mutations. One tumor had 2 HIF2A missense mutations, one of which was previously described in a PPGL (c.1121 T>A, F374Y). The second patient had coexistence of somatic truncated mutations (c.1669 C>T, Q557*) in HIF2A together with a VHL mutation. Neither of the two patients had polycythemia at the time of diagnosis. We demonstrate that the novel truncated mutation in HIF2A (Q557*) affects HIF-2α prolyl hydroxylation with its reduced ubiquitination but intact transcriptional activity, resulting in an activating effect. Both CNS-HB samples showed positive expression of VEGFR2/CA9/Glut1 and HAF. Our data support the unique central role of the VHL/HIF-2α signaling pathway in the molecular pathogenesis of CNS-HBs and show for the first time the presence of HIF2A mutations in sporadic HB.
authors.affiliation: Department of Nuclear Medicine, La Timone University Hospital & CERIMED & Inserm UMR1068 Marseille Cancerology Research Center, Institut Paoli-Calmettes, Aix-Marseille University, 264 RUE Saint-Pierre, 13385, Marseille, France. david.taieb@ap-hm.fr.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
authors.affiliation: Laboratory of Molecular Biology, Conception Hospital & CNRS, CRN2M UMR 7286, Aix-Marseille University, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.affiliation: Laboratory of Molecular Biology, Conception Hospital & CNRS, CRN2M UMR 7286, Aix-Marseille University, Marseille, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Pertuit
authors.affiliation: Department of Neuropathology, La Timone University Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Tchoghandjian
authors.affiliation: Department of Endocrinology, La Timone University Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Rochette
authors.affiliation: Department of Genetics, La Timone University Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Zattara-Canoni
authors.affiliation: Department of Neuropathology, La Timone University Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Department of Neurosurgery, La Timone University Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Metellus
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018325:Hemangioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Hemangioblastoma; Hypoxia-inducible factor 2α; Von Hippel–Lindau syndrome