Plates-Formes de Recherche en Neurosciences

logo amu logo cnrs

Plates-formes PFRN

Accueil > Bibliographie > Somatic gain-of-function HIF2A mutations in sporadic central nervous system (...)

Somatic gain-of-function HIF2A mutations in sporadic (...)

J Neurooncol. 2016 Feb ;126(3):473-81
Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas.
Taieb D, Barlier A, Yang C, Pertuit M, Tchoghandjian A, Rochette C, Zattara-Canoni H, Figarella-Branger D, Zhuang Z, Pacak K, Metellus P.

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.

PubMed

    Ils nous font confiance

  • logo amu
  • logo cnrs
  • logo inserm
  • logo AP-HM
  • logo F�d�ration pour la Recherche sur le Cerveau
  • logo Fondation pour la Recherche Medical en France
  • logo IBiSA
  • logo Europe programme FEDER
  • logo Agence Nationale de la Recherche
  • logo Plateforme Technologique Aix-Marseille
  • logo Vect-Horus
  • logo Neuron Experts