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

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.