Molecular subtypes of glioblastoma are relevant to lower grade glioma

Abstract

Background: Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas).

Methods: Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al.

Results: Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.

Conclusions: GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.

Figure 1. Overall analysis approach.

Figure 2. Heatmaps for the Verhaak 840-gene expression based subtype by histological group and IDH1/G-CIMP status in the Rembrandt, JCO and DASL datasets.

Figure 3. Survival analysis of gene expression subtype and IDH1/G-CIMP status by histological group and by grade of tumor adjusted for age at diagnosis.

Merged dataset of JCO, Rembrandt and DASL (A: Oligo II& III (N = 46); B: Astro II & III (N = 132); C: GBM (N = 387); D: Grade II(N = 71); E: Grade III (N = 107)).

Figure 4. Somatic copy number analysis for Rembrandt dataset by histological group, gene expression subtype and IDH1/G-CIMP status (p values were accessed via fisher’s exact test).