SummaryWe collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Purpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG). Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib. Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model. Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children. (Clin Cancer Res 2009;15(18):5753-61) Amplification, overexpression, and/or mutation of the epidermal growth factor receptor (EGFR) represent a compelling set of molecular genetic indicators for targeted therapy in adult glioblastoma. About 40% of glioblastomas show amplification of the EGFR gene locus, and about half of these tumors express a mutant receptor (EGFRvIII) that is constitutively active due to an in-frame truncation within the extracellular ligand-binding domain (1). In addition, novel missense mutations have been reported in the extracellular domain of tumors and cell lines (2), and recently, additional mutations have been described outside of these regions (e.g., in the transmembrane domains), although the significance of these is not yet clear (3).EGFRvIII is caused by deletion of exons 2 to 7, resulting in a protein that lacks a ligand-binding domain and is constitutively activated and is further resistant to down-regulation due to a low rate of receptor endocytosis (4). EGFRvIII has been shown

Perfusion-weighted imaging is a feasible method of reducing the sampling error in the histopathological diagnosis of a presumed LGG, particularly by improving the selection of targets for stereotactic biopsy.

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High grade gliomas (HGG) are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI) in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults) using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR. DNA copy number profiles were derived using array CGH, and mutations in eighteen MSI target genes studied by multiplex PCR and genotyping. MSI was found in 14/71 (19.7%) pediatric cases, significantly more than observed in adults (5/73, 6.8%; p = 0.02, Chi-square test). MLH1 expression was downregulated in 10/13 cases, however no mutations or promoter methylation were found. MSH6 was absent in one pediatric MSI-High tumor, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and associated with a remarkably stable genomic profile. Of the eighteen classic MSI target genes, we identified mutations only in MSH6 and DNAPKcs and described a polymorphism in MRE11 without apparent functional consequences in DNA double strand break detection and repair. This study thus provides evidence for a potential novel molecular pathway in a proportion of gliomas associated with the presence of MSI.

Medulloblastoma has variable appearances on MRI in both children and adults. Adults are more likely to have heterogeneous cerebellar hemisphere tumours, and this is thought to be related to the greater prevalence of desmoplastic tumours in adulthood. Few studies have addressed the MRI features of adult medulloblastoma and the specific characteristics of desmoplastic and classic tumours have not been analysed. Our aim was to analyse the imaging characteristics of desmoplastic (DM) and classic (CM) medulloblastomas in adult. We retrospectively studied preoperative MRI of six men and three women, median age 33 years, range 23-53 years, with pathologically proved medulloblastomas. There were six (67%) with DM. The tumour was in the cerebellar hemisphere in eight patients (89%), including the three with CM, one of which was bilateral. All tumours were heterogeneous, giving predominantly low or isointense signal on T1- and isointense signal on T2-weighted images. Cystic or necrotic areas in all patients were particularly visible on T2-weighted images. Contrast enhancement was absent in one DM and varied from slight to intense in eight (three CM), homogeneous in one DM and patchy in seven. All tumours extended to the surface of the cerebellum and two had well-defined margins. MRI does not allow a clear distinction between DM and CM in adults.

Our aim was to retrospectively evaluate the influence of gemistocytic astrocytes, cellular proliferation indices, immunoexpression of proteins p53 and bcl-2 in the clinical outcome of 39 patients with WHO grade II and III astrocytomas with the presence of gemistocytes. The mean proportion of gemistocytes was 18.7% and the mean proliferative index was 3.3%. Immunoexpression of p53 was detected in 29 cases (74.4%) and all cases (100%) were positive for bcl-2. The median overall survival was 97.2 months and the progression-free survival was 43.1 months. Estimated 1-, 5- and 10-year overall survival rates were 94.3%, 69.5% and 46.4%; 1-, 5- and 10-year progression-free survival rates were 91.1%, 26.1% and 13.1%. Out of 24 who presented clinical and neuroimaging worsening, characterized as tumor progression or recurrence, 16 had histological confirmation and were also analyzed. We could not detect significant differences when comparing all the indices between WHO grade II and III and also between the first and second biopsies. We also could not detect significant differences in progression-free and overall survival when analyzing the gemistocyte index and the immunohistochemical labeling indices p53, bcl-2 and MIB-1, as well as patientsa9 age (median value, up to 34 vs. over 34 years) and histological grade (II or III). Our finding confirms recent reports that question the role of gemistocytes as a prognostic factor in diffuse astrocytomas. The significance and role of gemistocytes in astrocytomas has yet to be defined and warrants further study.

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