Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma

Abstract

A B S T R A C T PurposeLong-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and MethodsSingle-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. ResultsFrequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. ConclusionDIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.

Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features

“…In another genomic study of single-nucleotide polymorphisms in DIPG, 11 samples underwent analysis by a 250k SNPs array, which identified gains in PDGFRA in 36% of samples, and poly ADP-ribose polymerase (PARP-1) pathway genes in 27% of samples [173]. Furthermore, analysis of genome copy number abnormalities in 43 DIPGs and 8 low-grade brainstem gliomas demonstrated gene amplifications of the Ras/PI3K signalling pathway in 47% of tumours, the Rb cell-cycle regulatory pathway in 21% of tumours, and concurrent amplification in 21% of tumours [118]. PGFRA and MET were commonly up regulated genes.…”

Glioblastomas: are individual therapies required for individual tumors?

“…In children and adolescents, high grade gliomas do not only have a different biological behavior compared to those in adults [4,5,15,24], they also show other patterns of molecular alterations [68][69][70][71][72]. Pediatric tumors in average go along with longer survival -although cure is also a very rare event in them -and they are more often found in the posterior fossa, leading to a higher degree of complete resection [5].…”

“…Pediatric tumors in average go along with longer survival -although cure is also a very rare event in them -and they are more often found in the posterior fossa, leading to a higher degree of complete resection [5]. Further, the diffuse intrinsic pontine glioma (DIPG), a disease entity primarily defined by location in the pons and infiltrative growth behavior, is a disorder that is not at all observed in adults [5,24,70].…”

“…Also amplifications of genes controlling retinoblastoma protein (RB) phosphorylation are often seen [70]. In summary, to detect possible mechanisms defining drug sensitivity in glioblastiomas, pediatric tumors should in any case be regarded as a separate entity, and separate algorithms for response detection or prediction have to be defined [4,8,9,15].…”

Biopsy for diffuse intrinsic pontine glioma: a reappraisal

“…1,4,12,15 Furthermore, the majority of DIPGs have a particularly unique molecular signature, that of mutations in the histone genes, which leads to changes in gene expression that are believed to account for their oncogenesis. 3,9,14 In addition, pharmacological alterations in histone methylation appear to result in inhibition of tumor growth, at least in preclinical studies.…”