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During recent decades, the educational outcomes of the children of immigrants have been extensively studied, with a growing emphasis on the heterogeneity of the so-called second generation. Yet, the impact of host country citizenship on children's educational outcomes has only received limited attention so far, although children of immigrants do not get automatic birthright citizenship in most European countries. Focusing on the Netherlands, this paper compares educational trajectories among citizen and non-citizen children of immigrants. Register data and sequence analysis are used to map and cluster the trajectories of a full cohort of second-generation students from the start of secondary school. We apply a variant of optimal matching focusing on sequences of transitions, which enables us to uncover different patterns of (im)mobility within a stratified school system better than the standard approach. Multinomial logistic regressions show that students who acquire Dutch citizenship are significantly more likely to follow upward trajectories, taking advantage of the system's flexibility and "back doors". Conversely, not having Dutch citizenship is associated with a higher risk of dropout and school interruptions. These findings are in line with our theoretical expectation that, during the naturalisation process, parents acquire or further develop important resources for navigating a complex educational system such as the Dutch one., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In the context of 3D mapping, larger and larger point clouds are acquired with lidar sensors. Although pleasing to the eye, dense maps are not necessarily tailored for practical applications. For instance, in a surface inspection scenario, keeping geometric information such as the edges of objects is essential to detect cracks, whereas very dense areas of very little information such as the ground could hinder the main goal of the application. Several strategies exist to address this problem by reducing the number of points. However, they tend to underperform with non-uniform density, large sensor noise, spurious measurements, and large-scale point clouds, which is the case in mobile robotics. This paper presents a novel sampling algorithm based on spectral decomposition analysis to derive local density measures for each geometric primitive. The proposed method, called Spectral Decomposition Filter (SpDF), identifies and preserves geometric information along the topology of point clouds and is able to scale to large environments with a non-uniform density. Finally, qualitative and quantitative experiments verify the feasibility of our method and present a large-scale evaluation of SpDF with other seven point cloud sampling algorithms, in the context of the 3D registration problem using the Iterative Closest Point (ICP) algorithm on real-world datasets. Results show that a compression ratio up to 97 % can be achieved when accepting a registration error within the range accuracy of the sensor, here for large scale environments of less than 2 cm., (Copyright © 2020 Labussière, Laconte and Pomerleau.)

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10 -9 , odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10 -10 , OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10 -8 , OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10 -11 , OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10 -10 , OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10 -9 , OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10 -10 , OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10 -10 , OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10 -9 , OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10 -8 , OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10 -10 , OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10 -11 , OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10 -9 , OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Background: The 1p19q non-codeleted gliomas with IDH mutation, defined as "molecular astrocytomas," display frequent TP53 mutations and have an intermediate prognosis. We investigated the prognostic impact of copy number-neutral loss of heterozygosity (CNLOH) in 17p in this population., Methods: We analyzed 793 gliomas (206 grade II, 377 grade III, and 210 grade IV) by single nucleotide polymorphism array and for TP53 mutations., Results: Homodisomy revealed by CNLOH was observed in 156 cases (19.7%). It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 × 10(-16)), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001). In the group of IDH-mutated 1p19q non-codeleted gliomas, CNLOH 17p was associated with longer survival (86.3 vs. 46.2 months; p = .004), particularly in grade III gliomas (overall survival >100 vs. 37.9 months; p = .007). These data were confirmed in an independent dataset from the Cancer Genome Atlas., Conclusion: CNLOH 17p is a prognostic marker and further refines the molecular classification of gliomas., Implications for Practice: Homodisomy of chromosome 17p (CNLOH 17p) is a frequent feature in IDH-mutated 1p19q non-codeleted gliomas (group 2). It is constantly associated with TP53 mutation. It was found, within this specific molecular group of gliomas (corresponding to molecular astrocytomas), that CNLOH 17p is associated with a much better outcome and may therefore represent an additional prognostic marker to refine the prognostic classification of gliomas., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.

Purpose: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM., Experimental Design: We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models., Results: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μmol/L vs. 21.9 μmol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μmol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μmol/L). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival., Conclusions: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified., (©2015 American Association for Cancer Research.)

TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status.

Despite encouraging response rate of bevacizumab (BVZ) in recurrent glioblastoma, many patients do not respond to this schedule and most of the responders develop an early relapse. Plasma concentrations of VEGF, PlGF, Ang2, and sTie2 were assessed by ELISA before and during BVZ treatment in seventy patients. Baseline levels of VEGF-A, and PlGF were higher in patients than in healthy volunteers, whereas no difference was found for Ang2, and sTie2. No biomarker at baseline was associated with response, PFS or OS. At recurrence, the authors observed an increase of Ang2 suggesting that Ang2/sTie2 could be involved in the resistance to BVZ.

Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20-31%, P = 1.15 × 10(-17)) for all forms of glioma - 26% (95% CI: 17-35%, P = 1.05 × 10(-8)) for glioblastoma multiforme (GBM) and 25% (95% CI: 17-32%, P = 1.26 × 10(-10)) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified.

Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10(-11)), 12q21.2 (rs12230172, P=7.53 × 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes.

Objective: CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood., Methods: We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expression of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1(R132H) cells transfected with lentivirus encoding mutant and WT CIC., Results: We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p = 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation of normally CIC repressed genes ETV1, ETV4, ETV5, and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1(R132H) and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1., Interpretation: CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma., (© 2015 American Neurological Association.)

Objective: To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs)., Methods: We sequenced the TERTp-mut in DNA from 395 GBMs and analyzed the results with their respective histology, genetic profile (IDH1 mutation, EGFR amplification, CDKN2A homozygous deletion, loss of chromosome 10, TP53 mutation), and overall survival (OS)., Results: TERTp-mut were found in 299 of 395 GBMs (75.7%) and were associated with an older age (median 59.6 years for TERTp-mut vs 53.6 years for TERT promoter wild type [TERTp-wt], p < 0.0001). TERTp-mut was an independent factor of poor prognosis (OS = 13.8 vs 18.4 months), in both IDH-mutated (OS = 13.8 vs 37.6 months, p = 0.022) and IDH-wt GBMs (OS = 13.7 vs 17.5 months, p = 0.006). TERTp-mut was associated with IDH-wt, EGFR amplification, CDKN2A deletion, and chromosome 10q loss, but not with MGMT promoter methylation. In the TERTp-wt group, OS was twice longer in EGFR-wt than in EGFR amplification GBMs (OS = 26.6 vs 13.3 months; p = 0.005). In the EGFR-wt group, patients with TERTp-wt had a significantly better outcome (OS = 26.3 vs 12.5 months, p < 0.0001), whereas in the EGFR amplification group, patients with TERTp-mut survived longer (OS = 15.8 vs 13.3 months, p = 0.05). Taken together, the absence of both EGFR amplification and TERTp-mut is associated with longer survival in patients with GBM (26.5 months for patients with IDH-wt, 36.7 months for patients with IDH mutation)., Conclusions: The analysis of TERTp-mut, in combination with EGFR amplification and IDH mutation status, refines the prognostic classification of GBMs., (© 2014 American Academy of Neurology.)

Diffuse intrinsic brainstem gliomas (DIBG) account for 1-2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9-65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p < 0.01). IDH1 sequencing revealed two mutations (IDH1 (R132G) , IDH1 (R132C) ) out of 7 DIBG whereas the R132H IDH1 enzyme was detected in 1/17 DIBG, suggesting that IDH1 mutations are mostly non R132H in DIBG (2/2), in contrast to supratentorial gliomas (31/313; p = 0.01). Mutations in histone genes H3F3A (encoding H3.3) and HIST1H3B (encoding H3.1) were found in 3/8 (37.5 %) of the DIBG (two H3F3A (K27M) and one HIST1H3B (K27M) ) versus 6/205 (2.9 %) of the supratentorial high-grade gliomas (four H3F3A (G34R) and two H3F3A (K27M) ) (p = 0.002). The CGH array showed a higher frequency of chromosome arm 1q gain, 9q gain and 11q loss in DIBG compared to the supratentorial high-grade gliomas, which had a less frequent chromosome 7 gain, and a less frequent chromosome 10 loss. No EGFR amplification was found. These data suggest that adult DIBG differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare.

Objective: IDH1 codon 132 mutation (mostly Arg132His) is frequently found in gliomas and is associated with longer survival. However, it is still unclear whether IDH1 mutation renders the cell more vulnerable to current treatment, radio- and chemotherapy., Materials and Methods: We transduced U87 with wild type IDH1 or IDH1 (R132H) expressing lentivirus and analyzed the radiosensitivity (dose ranging 0 to 10 Gy) under normoxia (20% O2) and moderate hypoxia (1% O2)., Results: We observed that IDH1 (R132H) U87 cells grow faster in hypoxia and were more sensitive to radiotherapy (in terms of cell mortality and colony formation assay) compared to nontransduced U87 and IDH1 (wt) cells. This effect was not observed in normoxia., Conclusion: These data suggest that IDH1 (R132H) mutation increases radiosensitivity in mild hypoxic conditions.

IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated--which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.

Background: Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM). Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM., Materials and Methods: We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact., Results: In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF). By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation., Conclusion: A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance.

We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.

Chromosome arms 1p and 19q codeletion, corresponding to an unbalanced reciprocal translocation t(1;19)(q10;p10), is seen in oligodendroglial tumours and is associated with better prognosis and better chemosensitivity. BRAF abnormalities are observed in pilocytic astrocytomas (tandem duplication-rearrangement) and in pleomorphic xanthoastrocytomas (BRAF V600E mutation). The vast majority of primary or de novo glioblastomas exhibit genetic abnormalities disrupting the intracellular signaling pathways of: transmembrane tyrosine kinase receptors to growth factors and their downstream signaling pathways (i.e. NF1-RAS-RAF-MAPK and PTEN-PI3K-AKT-TSC-mTOR); RB and; TP53. IDH1 and IDH2 mutations are frequent in diffuse grade II and grade III gliomas and in secondary glioblastomas. They are diagnostic and favorable independent prognostic biomarkers. In contrast, they are rare in primary or de novo glioblastomas and not reported in pilocytic astrocytomas. Germlin mutations in MSH2/MLH1/PMS2/MSH6, CDKN2A, TSC1/TSC2, PTEN, TP53 and NF1/NF2 predispose to glial tumors in the setting of hereditary cancer predisposition syndromes. Single nucleotide polymorphisms in TERT,CCDC26, CDKN2A/CDKN2B, RTEL, EGFR and PHLDB1 confer an inherited susceptibility to glial tumors., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 7 loci influencing glioma risk: rs2736100 (TERT), rs11979158 and rs2252586 (EGFR), rs4295627 (CCDC26), rs4977756 (CDKN2A/CDKN2B), rs498872 (PHLDB1), and rs6010620 (RTEL1)., Materials and Methods: We studied the relationship among these 7 glioma-risk SNPs and characteristics of tumors from 1374 patients, including grade, IDH (ie IDH1 or IDH2) mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, and 1p-19q codeletion., Results: rs2736100 (TERT) and rs6010620 (RTEL1) risk alleles were associated with high-grade disease, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, and 9p and 10q deletion; rs4295627 (CCDC26) and rs498872 (PHLDB1) were associated with low-grade disease, IDH mutation, and 1p-19q codeletion. In contrast, rs4977756 (CDKN2A/B), rs11979158 (EGFR), and to a lesser extent, rs2252586 (EGFR) risk alleles were independent of tumor grade and genetic profile. Adjusting for tumor grade showed a significant association between rs2736100 and IDH status (P = .01), 10q loss (P = .02); rs4295627 and 1p-19q codeletion (P = .04), rs498872 and IDH (P = .02), 9p loss (P = .04), and 10q loss (P = .02). Case-control analyses stratified into 4 molecular classes (defined by 1p-19q status, IDH mutation, and EGFR amplification) showed an association of rs4295627 and rs498872 with IDH-mutated gliomas (P < 10(-3)) and rs2736100 and rs6010620 with IDH wild-type gliomas (P < 10(-3) and P = .03)., Conclusion: The frequency of EGFR and CDKN2A/B risk alleles were largely independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, and PHLDB1 variants were associated with different genetic profiles that annotate distinct molecular pathways. Our findings provide further insight into the biological basis of glioma etiology.

Background: The IDH1 gene, which encodes isocitrate dehydrogenase 1, is frequently mutated in gliomas and acute myeloid leukemia. The single-nucleotide polymorphism (SNP) (reference SNP no. rs11554137:C>T) located on IDH1 codon 105 has been associated with a poor outcome in patients with acute myeloid leukemia but has not been investigated in patients with gliomas., Methods: The IDH1 codon 105 SNP was genotyped first in a series of 952 patients with grade 2 through 4 gliomas and was correlated with outcomes and tumor genomic profile. Then, it was genotyped in 2 validations sets of 306 patients with glioblastoma (GBM) and 591 patients with glioma., Results: The minor allele codon 105 glycine (GGT) SNP (IDH1(105GGT) ) was identified in 98 of 952 patients (10.3%) and was not associated with the codon 132 (IDH1(132) ) mutation. Patients who had GMB with the IDH1(105GGT) variant had a poorer outcome than patients without the variant (median overall survival [OS], 10.7 months vs 15.5 months; P = .001; median progression-free survival [PFS], 6.4 months vs 8.5 months; P = .003). The prognostic impact was confirmed in an independent validation set of 306 GBMs from the same center (median PFS, 6.8 months vs 9.7 months; P = .006; median OS, 13.9 months vs 18.8 months; P = .0187). In the second validation cohort (591 grade 2-4 gliomas), a significant association was observed between IDH1(105GGT) and an adverse prognosis for the overall series and for patients with World Health Organization grade 3 gliomas, but the difference did not reach significance in patients with GBM., Conclusions: Taken together, the current data strongly suggested an association between the SNP rs11554137:C>T polymorphism and adverse outcomes in patients with malignant glioma. A single-nucleotide polymorphism (SNP) located on codon 105 of the isocitrate dehydrogenase 1 (IDH1) gene (reference SNP rs11554137) is analyzed in 3 independent series of patients with gliomas. The SNP rs11554137 is independent of the occurrence of somatic mutation on IDH1 codon 132, but, per se, has a prognostic impact in malignant gliomas., (Copyright © 2012 American Cancer Society.)

PDGFRA is a critical gene in glioma biology. Similar to EGFR, PDGFRA has been shown to be overexpressed, amplified, mutated, or truncated in gliomas, particularly glioblastomas. In addition, PDGFRA has been recently shown to be rearranged in glioblastoma. However, the frequency, cooccurrence, and clinical value of PDGFRA abnormalities in diffuse gliomas remain unclear. We investigated PDGFRA abnormalities and their clinical impact on 619 primary diffuse gliomas, including 167 grade II, 168 grade III, and 284 grade IV gliomas, with use of BAC-aCGH and validated our findings by quantitative polymerase chain reaction (PCR). We studied PDGFRA expression using reverse-transcription quantitative PCR in 84 gliomas and 12 non-tumor samples. In 138 samples, we also screened PDGFRA point mutations in exons 5, 7, 8, 9, 10, 11, and 23; presence of KDR-PDGFRA fusion gene; and PDGFRA truncation. PDGFRA was amplified and gained in 5.2% and 1.9% of samples, respectively. In addition PDGFRA was point-mutated, rearranged, and truncated in 2.9%, 0%, and 0.7% of cases, respectively. PDGFRA point mutations were observed exclusively in grade IV gliomas and in 12.5% of PDGFRA-amplified tumors. High-level PDGFRA amplification was associated with PDGFRA overexpression, high malignancy grade, and older patient age. Of interest, high-level PDGFRA amplification has an independent negative prognostic value for progression-free survival and overall survival among patients with grade III tumors. PDGFRA is altered through various genetic mechanisms in a subset of high-grade gliomas in patients who might be ideal candidates for PDGFRA inhibitor treatment, and PDGFRA gene amplification could be used as a prognostic biomarker in anaplastic gliomas.

Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans., Methods:   We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets., Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing or conducting meta-analysis. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians., Conclusion: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.

Background: There is a strong need to determine the best technique for O(6) -methylguanine-DNA-methyltranferase (MGMT) analysis, because MGMT status is currently used in clinical trials and occasionally in routine clinical practice for glioblastoma patients., Methods: The authors compared analytical performances and predictive values of 5 techniques in a series of 100 glioblastoma patients who received standard of care treatment (Stupp protocol)., Results: MGMT promoter was considered methylated in 33%, 33%, 42%, and 60% of patients by methylation-sensitive high-resolution melting, MethyLight, pyrosequencing (with an optimal risk cutoff at 8% for the average percentage of the 5 CpGs tested), and methylation-specific polymerase chain reaction (MS-PCR), respectively. Fifty-nine percent of the samples had <23% (the optimal risk cutoff) of MGMT-positive tumor cells. The best predictive values for overall survival (OS), after adjustment for age and performance status, were obtained by pyrosequencing (hazard ratio [HR], 0.32; P < .0001), MS-PCR (HR, 0.37; P < .0001), and immunohistochemistry (HR, 0.43; P = .0005) as compared with methylation-sensitive high-resolution melting (HR, 0.52 P = .02) and MethyLight (HR, 0.6; P = .05). For progression-free survival (PFS), the best predictive values were obtained with pyrosequencing (HR, 0.35; P < .0001), methylation-sensitive high-resolution melting (HR, 0.46; P = .002), and MS-PCR (HR, 0.49; P = .002). Combining pyrosequencing and immunohistochemistry slightly improved predictive power for OS, but not for PFS. Poor reproducibility and interobserver variability were, however, observed for immunohistochemistry., Conclusions: Good prediction of survival in addition to high reproducibility and sensitivity made pyrosequencing the best among the 5 techniques tested in this study., (Copyright © 2012 American Cancer Society.)

Gliomatosis cerebri (GC) constitutes a heterogeneous group of conditions involving diffuse neoplastic glial cell infiltration of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression, which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective series of 40 GC treated with up-front chemotherapy, we analyzed IDH1(R132H) mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1(R132H) and 10/40 GC expressed INA. IDH1(R132H) staining was strongly related to progression-free survival (42.3 vs. 15.5 months for positive IDH1(R132H) vs. negative tumors; P < 0.0001) and overall survival (73.9 vs. 23.6 months; P < 0.0001). This effect was independent of grade, histologic subtype, and INA expression (P < 0.001). Combined expression of IDH1(R132H) and INA was strongly associated with response to chemotherapy (100% vs. 36%; P = 0.003). These data strongly suggest that INA and IDH1(R132H) mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.

While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.

Purpose: To investigate the influence of the bortezomib (BTZ) on malignant glioma radiosensitivity in two xenograft models., Methods and Materials: For TCG3 and U87 models, we evaluated the antitumor activity of BTZ, radiotherapy, and BTZ plus radiothearapy according to two therapeutic schedules: a "nonfractionated" schedule corresponding to a single dose of treatment per week, and a "fractionated" schedule corresponding to the same weekly dose divided into 5 fractions. Treatments influence on proliferation and apoptosis indexes, cell cycle distribution, and nuclear factor-κB pathway were explored., Results: The radiosensitizing properties of BTZ observed with the nonfractionated schedule were lost with the fractionated schedule. Bortezomib-mediated radiosensitization was associated with an increased apoptosis response and major changes in cell proliferation, but the nuclear factor-κB pathway was not involved. Most of the cellular effects induced by BTZ when tumors received a single irradiation were cancelled out if radiotherapy was fractionated., Conclusion: The influence of BTZ on glioma radiosensitivity seems to depend on the treatment fractionation schedule, emphasizing the need to clarify the mechanisms underlying BTZ's radiosensitizing effects before further clinical trials are initiated., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The p.Arg132His mutation of isocitrate dehydrogenase 1 (IDH1(R132H) ) is a frequent alteration and a major prognostic marker in gliomas. However, direct sequencing of highly contaminated tumor samples may fail to detect this mutation. Our objective was to evaluated the sensitivity of a newly described amplification method, coamplification at lower temperature-PCR (COLD PCR), combined with high-resolution melting (HRM) for the detection of the IDH1(R132H) mutation. To this end, we used serial dilutions of mutant DNA with wild-type DNA. PCR-HRM assay detects IDH1(R132H) at an abundance of 25%, similar to the detection limit of direct Sanger sequencing. Introducing a run of COLD PCR allows the detection of 2% mutant DNA. Using two consecutive runs of COLD PCR, we detected 0.25% mutant DNA in a background of wild-type DNA, that mimics a tumor sample highly contaminated by normal DNA. We then analyzed 10 biopsies of tumor edges, considered free of tumor cells by histological analysis, and showed that immunohistochemistry of IDH1(R132H) was positive in three cases (30%), whereas double COLD PCR HRM was positive in the 10 cases studied (100%). In summary, COLD PCR HRM analysis is 100-fold more sensitive than Sanger sequencing, rendering this rapid and powerful strategy particularly useful for samples highly contaminated with normal tissue., (© 2010 Wiley-Liss, Inc.)

Malignant glioma patients have a life expectancy reduced to about 15 months despite aggressive surgery, radiotherapy (RT), and chemotherapy. Doxorubicin has shown a marked cytotoxic effect against malignant glioma cells in vitro. The brain exposure to this drug is, however, hindered by the blood-brain barrier. Encapsulation of doxorubicin in liposomal carriers has been shown to reduce toxicities and to improve brain tumors exposure to doxorubicin. In this study, we evaluated the radiosensitizing properties of a nonpegylated liposomal doxorubicin (Myocet, MYO) on two subcutaneous (U87 and TCG4) and one intracranial (U87) malignant glioma models xenografted on nude mice. Doxorubicin biodistribution was assessed by a high-performance liquid chromatography method. Antitumor efficacy was investigated by tumor volume measurements and mice survival determination. We showed that (i) encapsulation of doxorubicin ensured a preferential deposition of doxorubicin in tumoral tissue in comparison with free doxorubicin; (ii) doxorubicin accumulated in both subcutaneous and intracranial tumors during repeated injections of MYO and this accumulation was linked to the potentiation of RT efficacy on two subcutaneous models; (iii) MYO was unable to improve the antitumoral efficacy of RT on an intracranial glioma model. Finally, this study emphasizes the importance of performing preclinical studies on models closer as possible of human tumors and localization to be more predictive of therapeutic effects observed in humans.