Farewell to GBM-O: Genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups

Abstract

Introduction: Glioblastoma with oligodendroglioma component (GBM-O) was recognized as a histologic pattern of glioblastoma (GBM) by the World Health Organization (WHO) in 2007 and is distinguished by the presence of oligodendroglioma-like differentiation. To better understand the genetic underpinnings of this morphologic entity, we performed a genome-wide, integrated copy number, mutational and transcriptomic analysis of eight (seven primary, primary secondary) cases.

Results: Three GBM-O samples had IDH1 (p.R132H) mutations; two of these also demonstrated 1p/19q co-deletion and had a proneural transcriptional profile, a molecular signature characteristic of oligodendroglioma. The additional IDH1 mutant tumor lacked 1p/19q co-deletion, harbored a TP53 mutation, and overall, demonstrated features most consistent with IDH mutant (secondary) GBM. Finally, five tumors were IDH wild-type (IDHwt) and had chromosome seven gains, chromosome 10 losses, and homozygous 9p deletions (CDKN2A), alterations typical of IDHwt (primary) GBM. IDHwt GBM-Os also demonstrated EGFR and PDGFRA amplifications, which correlated with classical and proneural expression subtypes, respectively.

Conclusions: Our findings demonstrate that GBM-O is composed of three discrete molecular subgroups with characteristic mutations, copy number alterations and gene expression patterns. Despite displaying areas that morphologically resemble oligodendroglioma, the current results indicate that morphologically defined GBM-O does not correspond to a particular genetic signature, but rather represents a collection of genetically dissimilar entities. Ancillary testing, especially for IDH and 1p/19q, should be used for determining these molecular subtypes.

Fig. 1

Photomicrographs of GBM-O cases. Images show representative areas of macrodissected tumor (H&E, 20×). In all cases, submitted tissue included regions of oligodendroglial differentiation

Fig. 2

Clinicopathologic features of GBM-O cases and results of targeted Fluidigm DNA sequencing. a Case details including previously obtained FISH (EGFR, 1p/19q) and IDH1 R132H immunohistochemistry results. *prior diagnosis was fibrillary astrocytoma, grade II b Nonsynonymous mutations were detected in 5/8 cases (12 missense, 1 nonsense). Numerals in boxes indicate number of mutations if more than one

Fig. 3

Patterns of recurrent copy-number aberrations (CNAs) identified using Illumina microarray. Focal amplifications of 7p11.2 (EGFR) and gains of chr7 were present in 4/8 and 6/8 cases, respectively, and were mutually exclusive of 1p/19q co-deletion and IDH1 R132H mutation (cases 1 and 2). Loss of chr10 (PTEN) and homozygous 9p21.3 loss (CDKN2A) occurred in 4/4 and 2/4 cases with EGFR amplification, respectively. Focal gains involving 4q12 (PDGFRA) were present in 2 cases

Fig. 4

Gene expression profile heat map. A positive enrichment score (column Z-score) indicates the tumor sample expression profile and the genes in that particular gene set are positively correlated, whereas a negative enrichment score indicates the opposite. Five tumors demonstrated expression signatures enriched for one subtype, while the remaining three had transcriptional profiles enriched for two. Three tumors showed exclusive classification as the proneural subtype (cases 1, 2, and 6), and one tumor each was classified exclusively as classical and mesenchymal (cases 7 and 3, respectively). Cases 4 and 5 showed both classical and neural signatures, while case 8 showed both mesenchymal and neural subtype expression patterns

Fig. 5

Overview of molecular aberrations in GBM-O cases. Each column represents a single case and cases are grouped by expression signature subtype. In regards to EGFR and PDGFRA alterations, red boxes indicate samples demonstrated both DNA amplification and high-level gene expression, whereas samples with dark grey boxes showed only amplification. Light grey boxes indicate negative for mutation or balanced chromosomal status