Gene Expression Profiling Stratifies IDH1-Mutant Glioma with Distinct Prognoses

Isocitrate dehydrogenase (IDH) 1 mutation is one of the most important genetic aberrations in glioma. Even several genetic events have refined its prognostic value, the genome-wide expression alteration has not been systematically profiled. In this work, RNA-seq expression data from 310 patients in the Chinese Glioma Genome Atlas database were included as training set, while another 297 patients with microarray data were used as internal validation set. An independent cohort of GSE16011 (n = 205) constituted an external validation set. Approximately one fifth of the genes were differentially expressed in LGG according to IDH1 mutation status, yielding distinct gene expression profiles. A six-gene risk signature was established for IDH1-mutant LGG to distinguish low-from high-risk cases, which had distinct prognoses. The six-gene signature was an independent prognostic factor for IDH1-mutant LGG and had superior predictive value as compared to traditional clinicopathologic factors. Moreover, we depicted the differential expression pattern in GBM attributing to various IDH1 status, which was similar to that of LGG. It suggested that the effect of IDH1 mutation is conserved across histological classifications. The six-gene signature had equal prognostic value for IDH1-mutant GBM. By combining glioma grade, IDH1 status, and the six-gene signature, all glioma patients could be classified into six subgroups. These six subgroups could be further summarized into three sets with distinct prognosis. Taken together, a gene expression profile associated with IDH1 status was identified in LGG and GBM; a risk signature based on six genes was developed with equal prognostic value for IDH1-mutant LGG and GBM. When combined with clinicopathologic factors, the six-gene signature is a tool that enables precise risk stratification and can improve clinical management.