Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

Purpose:Isocitratedehydrogenase(IDH)genemutationsoccurinlow-gradeandhigh-gradegliomas.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 into mouse brains and genotyped all resection specimens using a CLIA-certified molecular 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 xenograft- producing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocy- toma), and6of 8additionally hadactivatingmutationsinPIK3CAoramplification ofPDGFRA,MET,orN- MYC. Only IDH1 andCIC/TP53 mutations were detected in non-xenograft-forming gliomas (P ¼0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterationsinknowncancerdrivergenesin13.4%ofIDH-mutantgliomapatients,includingPIK3CA,KRAS, AKT ,o rPTEN mutation or PDGFRA, MET ,o rN-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET ampli- fication. Presence of driver alterations at progression was associated with shorter subsequent progression- free survival (median 9.0 vs. 36.1 months; P ¼ 0.0011). Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898-909. � 2014 AACR.