Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.

Background: Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or amplification (chr7+/chr10-/amp). Overall survival (OS) is 15 months after treatment.

RNA-sequencing of IDH-wild-type glioblastoma with chromothripsis identifies novel gene fusions with potential oncogenic properties.

Glioblastoma (GBM) is the most frequent and most aggressive form of glioma. It is characterized by marked genomic instability, which suggests that chromothripsis (CT) might be involved in GBM initiation. Recently, CT has emerged as an alternative mechanism of cancer development, involving massive chromosome rearrangements in a one-step catastrophic event.

Whole genome duplication is an early event leading to aneuploidy in -wild type glioblastoma.

Glioblastoma, the most frequent and lethal form of glioma, displays chromosome instability and recurrent somatic copy number alterations (SCNA). Chromothripsis and whole genome duplication (WGD) have been recently identified in cancer. In the present study, we analyzed SCNA and determine the ploidy pattern in 123 -wild-type glioblastomas, using SNP array data.

Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma.

Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq).

Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study.

BRAF-V600E immunohistochemistry in a large series of glial and glial-neuronal tumors.

Introduction: Some glial-neuronal tumors (GNT) (pleomorphic xantho-astrocytoma [PXA], ganglioglioma [GG]) display BRAF-V600E mutation, which represents a diagnostic clue to these entities. Targeted therapies against BRAF-V600 protein have shown promising results in GNT. The aim of this study was to assess the utility of BRAF-V600E immunohistochemistry (IHC, clone VE1) in daily practice in a series of 140 glial, and GNT compared to molecular biology (MB) techniques.

Chromosome 17p Homodisomy Is Associated With Better Outcome in 1p19q Non-Codeleted and IDH-Mutated Gliomas.

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.

Severe hydrocephalus caused by diffuse leptomeningeal and neurocutaneous melanocytosis of antenatal onset: a clinical, pathologic, and molecular study of 2 cases.

Diffuse leptomeningeal melanocytosis (DLM) is a rare nevomelanocytic proliferation arising in the meninges. Despite their lack of morphological features of malignancy, these clonal nevomelanocytic cells are capable of extensive invasion and of malignant behavior. When associated with congenital melanocytic nevi, the disorder is named neurocutaneous melanocytosis (NCM).

Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.

Purpose: Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency and molecular features of FGFR-TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma.

Experimental Design: Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile.

VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab.

Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ.

TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.

Background: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.

Methods: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples.

Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes.

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.

Mutational analysis of primary central nervous system lymphoma.

Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence.

A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma.

Introduction: Mutations in isocitrate dehydrogenase genes IDH1 or IDH2 are frequent in glioma, and IDH mutation status is a strong diagnostic and prognostic marker. Current IDH mutation screening is performed with an immunohistochemistry (IHC) assay specific for IDH1 R132H, the most common mutation. Sequencing is recommended as a second-step test for IHC-negative or -equivocal cases.

IDH mutations: genotype-phenotype correlation and prognostic impact.

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.

Tumor and endothelial cell hybrids participate in glioblastoma vasculature.

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.

An ANOCEF genomic and transcriptomic microarray study of the response to irinotecan and bevacizumab in recurrent glioblastomas.

Background: We performed a retrospective study to assess whether the initial molecular characteristics of glioblastomas (GBMs) were associated with the response to the bevacizumab/irinotecan chemotherapy regimen given at recurrence.

Results: Comparison of the genomic and gene expression profiles of the responders (n = 12) and nonresponders (n = 13) demonstrated only slight differences and could not identify any robust biomarkers associated with the response. In contrast, a significant association was observed between GBMs molecular subtypes and response rates.

Clinical value of chromosome arms 19q and 11p losses in low-grade gliomas.

Background: Diffuse low-grade gliomas (LGGs) form a heterogeneous subgroup of gliomas in adults. Chromosome (chr) arms 1p/19q codeletion and IDH mutation have been shown to be closely associated with oligodendroglial phenotype and better prognosis. We sought to identify relevant biomarkers in non 1p/19q codeleted LGGs.

Ongoing and prolonged response in adult low-grade gliomas treated with radiotherapy.

The aim of the present study was to evaluate the impact of first-line radiotherapy on low-grade gliomas (LGGs) growth kinetics. The mean tumor diameter (MTD) of 39 LGGs was retrospectively measured on serial magnetic resonance images before (n = 16) and after radiotherapy onset (n = 39). After radiotherapy, a decrease of the MTD was observed in 37 patients.

Deciphering the 8q24.21 association for glioma.

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.

Interlaboratory comparison of IDH mutation detection.

Isocitrate dehydrogenase (IDH) mutational testing is becoming increasingly important. For this, robust and reliable assays are needed. We tested the variation of results between six laboratories of testing for IDH mutations.

Prognostic impact of the isocitrate dehydrogenase 1 single-nucleotide polymorphism rs11554137 in malignant gliomas.

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.

Association between glioma susceptibility loci and tumour pathology defines specific molecular etiologies.

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.