A Genome-Wide Profiling of Glioma Patients with an IDH1 Mutation Using the Catalogue of Somatic Mutations in Cancer Database

SIMPLE SUMMARY: Glioma patients that present a somatic mutation in the isocitrate dehydrogenase 1 (IDH1) gene have a significantly better prognosis and overall survival than patients with the wild-type genotype. An IDH1 mutation is hypothesized to occur early during cellular transformation and leads to further genetic instability. A genome-wide profiling of glioma patients in the Catalogue of Somatic Mutations in Cancer (COSMIC) database was performed to classify the genetic differences in IDH1-mutant versus IDH1-wildtype patients. This classification will aid in a better understanding of how this specific mutation influences the genetic make-up of glioma and the resulting prognosis. Key differences in co-mutation and gene expression levels were identified that correlate with an improved prognosis. ABSTRACT: Gliomas are differentiated into two major disease subtypes, astrocytoma or oligodendroglioma, which are then characterized as either IDH (isocitrate dehydrogenase)-wild type or IDH-mutant due to the dramatic differences in prognosis and overall survival. Here, we investigated the genetic background of IDH1-mutant gliomas using the Catalogue of Somatic Mutations in Cancer (COSMIC) database. In astrocytoma patients, we found that IDH1 is often co-mutated with TP53, ATRX, AMBRA1, PREX1, and NOTCH1, but not CHEK2, EGFR, PTEN, or the zinc finger transcription factor ZNF429. The majority of the mutations observed in these genes were further confirmed to be either drivers or pathogenic by the Cancer-Related Analysis of Variants Toolkit (CRAVAT). Gene expression analysis showed down-regulation of DRG2 and MSN expression, both of which promote cell proliferation and invasion. There was also significant over-expression of genes such as NDRG3 and KCNB1 in IDH1-mutant astrocytoma patients. We conclude that IDH1-mutant glioma is characterized by significant genetic changes that could contribute to a better prognosis in glioma patients.