François Labrousse

Clinical epidemiology for childhood primary central nervous system tumors

This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0–19xa0years) of newly diagnosed and histologically confirmed PCNST (during the years 2004–2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST.

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression

BACKGROUNDnThe aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs).nnnMETHODSnThe MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays.nnnRESULTSnMost of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2.nnnCONCLUSIONnIn AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas

Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations). To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named “Prise en charge des OLigodendrogliomes Anaplasiques (POLA),” has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively. At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD. Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas

Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours.

Clear cell ependymoma with trisomy 19 developing bone metastases

Ependymoma is the third most common pediatric brain tumor and accounts for 10% of childhood central nervous system tumors [1]. It is a neuroepithelial neoplasm arising from the ependymal layers of the brain and spinal cord. Ependymomas usually relapse at the original tumor site but may also relapse at other central nervous system sites due to leptomeningeal spread via the cerebrospinal fluid pathways [2]. Extraneural metastases are however extremely rare. Such metastases occur mainly in the lung, pleura, liver, and lymph nodes [3]. According to the best of our knowledge, only two previous cases of bone metastases have been reported [2, 4]. Here, we report a case of intracranial anaplastic ependymoma metastasizing in the brain, pleura, and bones. Case report

IDH2 mutations are commonly associated with 1p/19q codeletion in diffuse adult gliomas

716 IDH2 mutations are commonly associated with 1p/19q codeletion in diffuse adult gliomas Diffuse gliomas are classified according to the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System, 1 which combines histological and molecular features. Diagnosis requires the assessment of mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2), key genetic alterations characterizing gliomas with favorable outcome. 2 Because IDH1 and IDH2 are highly similar enzymes, the WHO classification, as most of the current studies, combines these mutations into the same molecular group; however, it is unclear whether these tumors share the same characteristics. We analyzed data from 1517 patients included in the French POLA Network to investigate differences between IDH1-and IDH2-mutant gliomas. Inclusion criteria were the written consent of the patient for clinical data collection and genetic analysis and sufficient material for molecular studies allowing classification according to the 2016 WHO classification. IDH1-R132H mutational status was evaluated using automated immunohistochemistry in all cases (n = 1517). Direct sequencing 3 was performed in 978 cases and demonstrated IDH mutation in 573 cases (this includes confirmation of IDH1-R132H mutation in 468 cases, other IDH1 mutations in 61 cases, and IDH2 mutation in 44 cases). The 1p/19q codeletion status was determined based on single nucleotide polymor-phism arrays, comparative genomic hybridization arrays, and/ or microsatellite marker analysis. 3 The following data were recorded: age, sex, follow-up, and MRI features (tumor location , extension, contrast enhancement, edema). All statistical analysis was done using IBM SPSS statistics software version 23. Chi-square test was used to compare qualitative variables. Continuous variables were compared using the Mann– Whitney U-test, and the Kaplan–Meier method was used to estimate survival distributions. Among the 1517 patients, 1025 had an IDH-mutant tumor: 96% were IDH1-mutant and 4% IDH2-mutant. Integrated diagnoses are summarized in Fig. 1. The frequency of 1p/19q code-letion was higher in the IDH2-mutant group compared with the IDH1-mutant group (91% vs 48%, P < 0.001). Wang and coworkers previously reported higher frequency of 1p/19q codeletion in IDH2-mutant gliomas (9/18 samples) compared with IDH1-mutant. 4 The percentage of each category in our study does not reflect the normal distribution of glioma because of the inclusion criteria in the POLA Network (ie, high-grade glioma with oligodendroglial component). However, the higher proportion of 1p/19q codeleted glioma in the IDH2-mutant group cannot be attributed to the inclusion criteria. Because the main population of glioma associated with IDH2 mutation was 1p/19q codeleted anaplastic oligodendroglioma, we focused on this subgroup to search for differences compared with IDH1 mutation. Among these patients (n = 474), we did not observe any difference in terms of age, sex, progression free survival, or overall survival between IDH1-and IDH2-mutant tumors. However, IDH2-mutant anaplastic oli-godendrogliomas presented more frequently with multilobar extension (56% of the IDH2-mutant vs 35% of the IDH1-mutant, P = 0.015) and edema (79% vs 57%, P = 0.02). Furthermore, bifrontal location with corpus callosum involvement was more frequent in IDH2-mutant compared with IDH1-mutant tumors (41% vs 16%, P < 0.001). IDH mutation is supposed to be one of the first hits of gliomagenesis, 5 resulting in production of an oncome-tabolite, D-2-hydroxyglutarate (D-2HG), which impacts the α-ketoglutarate–dependent dioxygenase functions. Previous studies demonstrated that the potential for IDH-mutant enzymes to produce D-2HG depends on the mutation type. 6 Based on our observations, we could hypothesize that the higher D-2HG accumulation induced by IDH2 mutation may lead to a phenotype that is favorable to 1p/19q chromosomal loss. It may also impact distinct cellular pathways that promote a more invasive phenotype. Whether IDH1 or IDH2 mutations impact distinct glial precursor cells with differential invasive properties remains to be elucidated. In conclusion, our results illustrate that IDH2-mutant glio-mas are commonly associated with 1p/19q codeletion. Most of IDH2-mutant anaplastic oligodendroglioma 1p/19q codeleted are multilobar. Understanding the genomic events involved in these specificities may represent a step forward for therapeutic development.