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

The integrin 6{beta}4 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 (IDHmut) 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 {beta}4 and malignant behavior in gliomas. An inverse relationship was identified between IDHmut and integrin {beta}4 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 IDHmut 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 IDHmut tumors, but fully account for the lower ITGB4 expression observed in IDHmut gliomas. In fact, ITGB4 is one of the most downregulated genes in IDHmut 1p/19q co-deleted gliomas compared to IDHmut 1p/19q intact gliomas (P = 3.2x10-39). In patient-derived glioma cells, we found that integrin {beta}4 is enriched in the stem-like population, and that knockdown of integrin {beta}4 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 {beta}4 increases glioma malignancy, and that its relative paucity may contribute to the better prognosis in IDH1/2 mutant, 1p/19q co-deleted oligodendrogliomas.