Human Cancer Biology Targetable SignalingPathwayMutationsAreAssociatedwith Malignant Phenotype in IDH-Mutant Gliomas

Purpose: Isocitrate dehydrogenase (IDH) genemutations occur in low-grade andhigh-grade gliomas.We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections intomouse brains and genotyped all resection specimens using a CLIA-certifiedmolecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograftproducing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activatingmutations in PIK3CA or amplification of PDGFRA,MET, orNMYC. Only IDH1 and CIC/TP53mutations were detected in non–xenograft-forming gliomas (P1⁄4 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4%of IDH-mutant gliomapatients, including PIK3CA,KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRASmutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progressionfree survival (median 9.0 vs. 36.1 months; P 1⁄4 0.0011). Conclusion: A subset of IDH-mutant gliomas withmutations in driver oncogenes has a moremalignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 1–12. 2014 AACR.