Abstract
BackgroundGliomas 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).MethodsGene 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.ResultsUnsupervised 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.ConclusionsGBM 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.
Highlights
Brain tumors contribute to a disproportionate share of cancerassociated morbidity and mortality
[13] Mechanistic studies found that this mutation produced 2-hydroxyglutarate and remodels the methylome. [15,16,17] The R132 IDH1 mutation, which was first reported in GBM, [18] is a prevalent event in lower grade gliomas and is a prognostic marker for better prognosis in both GII/IIIs and GBMs. [18,19,20,21] The better survival of GII/IIIs, especially those with the proneural subtype, has been attributed in large part to the distinctive genetic and clinical characteristics of IDH1 mutant tumors
[12] We aimed to evaluate the association between the five molecular subtypes and overall survival, using samples for which survival annotation was available from the JCO, Rembrandt and DASL datasets (Figure 3A, B, C, oligodendrogliomas: N = 46, astrocytomas: N = 132 and GBM: N = 387))
Summary
Brain tumors contribute to a disproportionate share of cancerassociated morbidity and mortality. [10,11,12,13] Multiple studies have utilized these types of genomic data for brain tumor stratification, for example, higher grade gliomas (grades III and IV) were divided into three groups based on their association with clinical outcome. [15,16,17] The R132 IDH1 mutation, which was first reported in GBM, [18] is a prevalent event in lower grade gliomas and is a prognostic marker for better prognosis in both GII/IIIs and GBMs. Similar subgrouping efforts based on genomic data for GII/IIIs have lagged behind, possibly due to the lower population incidence of these tumors as compared to GBMs. GII/IIIs represent an ensemble of diseases, including oliodendroglioma, astrocytoma and olioastrocytoma ( called mixed gliomas). 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)
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