Hypoxia-associated factor expression in low-grade and anaplastic gliomas: a marker of poor outcome

Abstract

// Aurelie Tchoghandjian 1, 2 , Mei Y. Koh 3 , David Taieb 1, 2, 4 , Sara Ganaha 6 , Garth Powis 3 , Emilie Bialecki 5 , Noel Graziani 5 , Dominique Figarella-Branger 1, 2, 6 , Philippe Metellus 2, 5 1 Aix-Marseille Universite, Faculte de Medecine, Marseille, 13385 Cedex 05, France 2 INSERM, UMR 911, CRO2, Faculte de Medecine, Marseille, 13385 Cedex 05, France 3 Sanford-Burham Medical Research Institute, Basic Laboratory Cancer Center, La Jolla, 92037 California, USA 4 Department of Nuclear Medicine, Assistance Publique-Hopitaux de Marseille, Hopital de la Timone, Marseille, 13385 Cedex 05, France 5 Department of Neurosurgery, Centre Hospitalier Clairval, Ramsay Generale de Sante, Marseille, 13009, France 6 Department of Neuropathology, Assistance Publique-Hopitaux de Marseille, Hopital de la Timone, Marseille, 13385 Cedex 05, France Correspondence to: Philippe Metellus, e-mail: Philippe.metellus@outlook.fr Keywords: low-grade gliomas, anaplastic gliomas, isocytrate deshydrogenase (IDH), hypoxia-inducible factor (HIF), hypoxia-associated factor (HAF) Received: September 10, 2015 Accepted: February 20, 2016 Published: March 14, 2016 ABSTRACT Somatic mutations in isocitrate dehydrogenase (IDH) genes have recently been identified in a large proportion of glial tumors of the CNS and reported to be a strong prognostic factor in gliomas whatever the tumor grade. Few data are available in the literature regarding the relationship between IDH mutations and HIF expression in low-grade gliomas (LGGs), especially in a recently described aggressive molecular subtype: “triple negative” (IDH non mutated, 1p 19q non codeleted, p53 expression negative) gliomas. We analyzed clinical, radiological and molecular features of a series of 31 grade II/III gliomas. p53 expression, 1p19q deletion and IDH mutation status were provided for all tumors. Also HIF (hypoxia inducible factor)-1α, HIF-2α, HAF, Sox2 (SRY(Sex determining region Y)-box2) and OCT (octamer binding factor) 3/4 expressions were analyzed. We found positive HIF-2α staining in 38.7% of cases which was uncorrelated to HIF-1α expression or IDH1/2 mutation status. However, HIF-2α staining was significantly associated with HAF expression, a stem-like cell marker, in the whole population. HAF expression was present in 74.2% of cases and significantly correlated to Sox2 expression. Furthermore, HAF expression was significantly associated with the “triple negative” glioma phenotype. We provide here first evidence that HAF, a stem-like cell marker, expression is highly correlated to the triple negative aggressive LGG/AG molecular phenotype suggesting that these tumours might arise from cells of different origin.