Integrin α6β4 is downregulated in mutant IDH1 oligodendrogliomas, promotes glioma growth, and associates with a worse outcome in glioma patients

The integrin α6β4 is a laminin receptor that associates with aggressive behavior in many cancers, though its significance in gliomas has not been established. Mutations in isocitrate dehydrogenase 1 and 2 (IDH mut ) are common in gliomas, especially 1p/19q co-deleted oligodendrogliomas, and correlate with improved patient survival. We sought to determine whether there is a link between integrin β4 and malignant behavior in gliomas. An inverse relationship was identified between IDH mut and integrin β4 expression in a glioma TMA ( P < 0.0001) and in TCGA grade II-IV gliomas ( P < 0.0001). Methylation of CpG sites in the ITGB4 promoter is significantly higher in IDH mut gliomas when compared to wild-type tumors, and both ITGB4 methylation and reduced ITGB4 mRNA are not only most prominent in the 1p/19q co-deleted subset of IDH mut tumors, but fully account for the lower ITGB4 expression observed in IDH mut gliomas. In fact, ITGB4 is one of the most downregulated genes in IDH mut 1p/19q co-deleted gliomas compared to IDH mut 1p/19q intact gliomas ( P = 3.2×10 -39 ). In patient-derived glioma cells, we found that integrin β4 is enriched in the stem-like population, and that knockdown of integrin β4 slows glioma growth in vitro ( P < 0.001) and in vivo (P = 0.01). Lower ITGB4 mRNA levels were also associated with longer overall survival in multiple patient cohorts ( P = 0.0005; P < 0.0001). These data suggest that integrin β4 increases glioma malignancy, and that its relative paucity may contribute to the better prognosis in IDH1/2 mutant, 1p/19q co-deleted oligodendrogliomas.