Publications by authors named "Yannick Marie"

92 Publications

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

Sci Rep 2021 05 13;11(1):10176. Epub 2021 May 13.

Service de Santé des Armées, Hôpital d'Instruction des Armées Percy, Service de Neurologie, 101 boulevard Henri Barbusse, 92140, Clamart, France.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.
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http://dx.doi.org/10.1038/s41598-021-89216-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119685PMC
May 2021

Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity.

Nat Cell Biol 2021 05 10;23(5):538-551. Epub 2021 May 10.

Université de Paris, INSERM U976, Paris, France.

COVID-19 can lead to life-threatening respiratory failure, with increased inflammatory mediators and viral load. Here, we perform single-cell RNA-sequencing to establish a high-resolution map of blood antigen-presenting cells (APCs) in 15 patients with moderate or severe COVID-19 pneumonia, at day 1 and day 4 post admission to intensive care unit or pulmonology department, as well as in 4 healthy donors. We generated a unique dataset of 81,643 APCs, including monocytes and rare dendritic cell (DC) subsets. We uncovered multi-process defects in antiviral immune defence in specific APCs from patients with severe disease: (1) increased pro-apoptotic pathways in plasmacytoid DCs (pDCs, key effectors of antiviral immunity), (2) a decrease of the innate sensors TLR9 and DHX36 in pDCs and CLEC9a DCs, respectively, (3) downregulation of antiviral interferon-stimulated genes in monocyte subsets and (4) a decrease of major histocompatibility complex (MHC) class II-related genes and MHC class II transactivator activity in cDC1c DCs, suggesting viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore the defective immune defence.
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http://dx.doi.org/10.1038/s41556-021-00681-2DOI Listing
May 2021

Impact of a frequent nearsplice variant in amyotrophic lateral sclerosis: optimising genetic screening for gene therapy opportunities.

J Neurol Neurosurg Psychiatry 2021 Sep 30;92(9):942-949. Epub 2021 Mar 30.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM,Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, Île de France, France

Objective: Mutations in superoxide dismutase 1 gene (, encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in non-coding sequences, is pathogenic.

Methods: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.

Results: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.

Conclusions: Our results highlighted nearsplice/intronic mutations in are responsible for a significant portion of French fALS and suggested the systematic analysis of the mRNA sequence could become the method of choice for screening, not to miss these specific cases.
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http://dx.doi.org/10.1136/jnnp-2020-325921DOI Listing
September 2021

Genetic screening of ANXA11 revealed novel mutations linked to amyotrophic lateral sclerosis.

Neurobiol Aging 2021 03 23;99:102.e11-102.e20. Epub 2020 Oct 23.

Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR7225, Sorbonne Université, UPMC Univ Paris 6 UMRS1127, Paris, France. Electronic address:

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.015DOI Listing
March 2021

IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification.

Neuro Oncol 2021 06;23(6):955-966

Sorbonne University, Brain and Spinal Cord Institute, Paris, France.

Background: Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined.

Methods: We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989-2020).

Results: Out of 517 grade II gliomas, 47 were "diffuse astrocytomas, IDHwt." Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%).

Conclusions: Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.
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http://dx.doi.org/10.1093/neuonc/noaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168809PMC
June 2021

Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease.

Front Neurol 2020 21;11:641. Epub 2020 Jul 21.

Sorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, France.

Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD. Thirty-six Parkinsonian patients on DA therapy with ( = 18) and without ICDs ( = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort. None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the "Adenylate cyclase activating" pathway, one of the top associated pathways in the discovery data set ( = 1.6 × 10) was replicated in the PPMI cohort and was significantly associated with ICDs in a pooled analysis (combined value 3.3 × 10). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in = 5 × 10; rs1877652 in = 8 × 10) although non-significant after Bonferroni correction. Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.
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http://dx.doi.org/10.3389/fneur.2020.00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385236PMC
July 2020

Initial surgical resection and long time to occurrence from initial diagnosis are independent prognostic factors in resected recurrent IDH wild-type glioblastoma.

Clin Neurol Neurosurg 2020 09 8;196:106006. Epub 2020 Jun 8.

Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, F-75013, Paris, France. Electronic address:

Objective: IDH wild-type glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized; several options include second surgery, reirradiation, and a second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated IDH wild-type glioblastoma patients below the age of 70 to see (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.

Methods: 229 newly diagnosed IDH wild-type glioblastoma patients below the age of 70 treated with the standard of care (SOC) were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection.

Results: All experienced tumor recurrence with a median progression-free survival of 11 months. 25 % of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and a long time from the initial diagnosis to the first recurrence were independent prognostic factors for good outcomes in resected recurrent IDH-wild-type glioblastoma patients; however, tumor size before and after surgery did not impact post-surgical survival.

Conclusion: Our study supports surgical resection at recurrence as therapeutic in IDH wild-type glioblastoma patients aged below 70 and in good clinical condition regardless of preoperative tumor size, particularly in patients who experienced a longer time before first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.
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http://dx.doi.org/10.1016/j.clineuro.2020.106006DOI Listing
September 2020

CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas.

Neuro Oncol 2019 12;21(12):1519-1528

Department of Pathological Anatomy and Neuropathology, Timone Hospital, Public Assistance-Marseille Hospitals (APHM), Marseille, France.

Background: The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification.

Methods: In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas.

Results: CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas.

Conclusions: Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.
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http://dx.doi.org/10.1093/neuonc/noz124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145561PMC
December 2019

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

Tremor Other Hyperkinet Mov (N Y) 2019 22;9. Epub 2019 Nov 22.

INSERM, U 1127, CNRS UMR 7225, Faculté de Médecine de Sorbonne Université, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, 75013 Paris, FR.

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches.

Methods: We first sequenced exons of and in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (, , and ) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (, , and ), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of in zebrafish.

Results: Thirteen ultrarare missense variants of and were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in , encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the orthologue in zebrafish induces a hyperkinetic phenotype in early development.

Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.
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http://dx.doi.org/10.7916/tohm.v0.693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878848PMC
September 2020

Juvenile myoclonic epilepsy phenotype in a family with Unverricht-Lundborg disease.

Epileptic Disord 2019 Aug;21(4):359-365

Razi Hospital, Department of Neurology, LR 18SP03, Tunis, Université de Tunis El Manar, Faculté de Médecine de Tunis, Tunis, Tunisia.

Unverricht-Lundborg disease (ULD), an autosomal recessive progressive myoclonus epilepsy, is due to an expansion, or less commonly a mutation, of the cystatin B (CSTB) gene. We report a clinical and molecular study of a Tunisian ULD family with five affected members presenting with a juvenile myoclonic epilepsy (JME)-like phenotype. The expansion of dodecamers was detected by a deamination/PCR assay. The expression profiles of CSTB and other candidate modifying genes, cathepsin B and cystatin C, were established by quantitative RT-PCR, and their respective transcription levels were compared with those from patients with a classic picture of ULD. Three patients had a fixed phenotype mimicking JME after 29 years of evolution. Only a discrete dysarthria was noticed in the two other patients. No correlation was observed between transcription level and severity of disease. Genetic screening should be performed in patients with a JME-like phenotype, when careful examination reveals discrete atypical signs of JME. This particular phenotype may be due to modifying genes and/or gene-environment interactions which require further clarification.
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http://dx.doi.org/10.1684/epd.2019.1078DOI Listing
August 2019

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations.

Oncologist 2019 12 25;24(12):1584-1592. Epub 2019 Jul 25.

Sorbonne Université, Inserm, CNRS, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France

Background: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.

Materials And Methods: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.

Results: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival ( = .021). Mitogen-activated protein kinase pathway alterations (including fusion, and mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.

Conclusion: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway.

Implications For Practice: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.
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http://dx.doi.org/10.1634/theoncologist.2019-0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975955PMC
December 2019

Machine Learning for Better Prognostic Stratification and Driver Gene Identification Using Somatic Copy Number Variations in Anaplastic Oligodendroglioma.

Oncologist 2018 12 17;23(12):1500-1510. Epub 2018 Jul 17.

Sorbonne Université, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France

Background: 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type.

Materials And Methods: A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables.

Results: Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: deletion, amplification, /MIR191 copy-neutral loss of heterozygosity, amplification, and amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment.

Conclusion: Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy.

Implications For Practice: Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.
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http://dx.doi.org/10.1634/theoncologist.2017-0495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292528PMC
December 2018

A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas.

Nat Commun 2018 06 18;9(1):2371. Epub 2018 Jun 18.

Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, F-75013, Paris, France.

Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCA mutation was not described in other tumors. PRKCA is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCα mRNA levels are more abundant than wild-type PKCα transcripts, while PKCα is less stable than the PCKα protein. Compared to PCKα, the PKCα protein is depleted from the cell membrane. The PKCα mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis.
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http://dx.doi.org/10.1038/s41467-018-04622-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006150PMC
June 2018

Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci.

Acta Neuropathol 2018 05 19;135(5):743-755. Epub 2018 Feb 19.

Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.

Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type). Most glioma risk loci showed subtype specificity: (1) the 8q24.21 SNP for triple-positive glioma; (2) 5p15.33, 9p21.3, 17p13.1 and 20q13.33 SNPs for TERT-only glioma; (3) 1q44, 2q33.3, 3p14.1, 11q21, 11q23.3, 14q12, and 15q24.2 SNPs for IDH mutated glioma. To link risk SNPs to target candidate genes we analysed Hi-C and gene expression data, highlighting the potential role of IDH1 at 2q33.3, MYC at 8q24.21 and STMN3 at 20q13.33. Our observations provide further insight into the nature of susceptibility to glioma.
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http://dx.doi.org/10.1007/s00401-018-1825-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904227PMC
May 2018

Amplification and Mutations in Glioblastoma Patients of the Northeast of Morocco.

Biomed Res Int 2017 13;2017:8045859. Epub 2017 Jul 13.

Pathological Anatomy and Molecular Pathology Service, University Hospital Hassan II of Fez, Fez, Morocco.

Glioblastomas are the most frequent and aggressive primary brain tumors which are expressing various evolutions, aggressiveness, and prognosis. Thus, the 2007 World Health Organization classification based solely on the histological criteria is no longer sufficient. It should be complemented by molecular analysis for a true histomolecular classification. The new 2016 WHO classification of tumors of the central nervous system uses molecular parameters in addition to histology to reclassify these tumors and reduce the interobserver variability. The aim of this study is to determine the prevalence of mutations and amplifications in the population of the northeast region of Morocco and then to compare the results with other studies. . codon 132 and codon 172 were directly sequenced and the amplification of exon 20 of gene was investigated by qPCR in 65 glioblastoma tumors diagnosed at the University Hospital of Fez between 2010 and 2014. . The R132H mutation was observed in 8 of 65 tumor samples (12.31%). No mutation of was detected. amplification was identified in 17 cases (26.15%). . A systematic search of both histological and molecular markers should be requisite for a good diagnosis and a better management of glioblastomas.
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http://dx.doi.org/10.1155/2017/8045859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530437PMC
April 2018

Same-day genomic and epigenomic diagnosis of brain tumors using real-time nanopore sequencing.

Acta Neuropathol 2017 11 21;134(5):691-703. Epub 2017 Jun 21.

Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Paris, France.

Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low-pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A, and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within 6 h and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas, and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2, and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations, and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource-restricted settings.
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http://dx.doi.org/10.1007/s00401-017-1743-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645447PMC
November 2017

Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

Brain Pathol 2017 Sep 28;27(5):567-579. Epub 2016 Oct 28.

POLA Network investigators: Amiens: Christine Desenclos, Henri Sevestre; Angers: Philippe Menei, Audrey Rousseau; Besançon: Joel Godard, Gabriel Viennet; Bobigny: Antoine Carpentier; Bordeaux: Sandrine Eimer, Hugues Loiseau; Brest: Phong Dam-Hieu, Isabelle Quintin-Roué; Caen: Jean-Sebastien Guillamo, Emmanuelle Lechapt-Zalcman; Clermont-Ferrand:Jean-Louis Kemeny, Toufik Khallil; Clichy: Dominique Cazals-Hatem, Thierry Faillot; Cornebarrieu: Ioana Carpiuc, Pomone Richard; Créteil: Caroline Le Guerinel; Colmar: Claude Gaultier, Marie-Christine Tortel; Dijon: Marie-Hélène Aubriot-Lorton, François Ghiringhelli; Kremlin-Bicêtre: Clovis Adam, Fabrice Parker; Lille: Claude-Alain Maurage, Carole Ramirez; Limoges: Edouard Marcel Gueye, François Labrousse; Lyon: Anne Jouvet; Marseille: Olivier Chinot; Montpellier: Luc Bauchet, Valérie Rigau; Nancy: Patrick Beauchesne, Dr Guillaume Gauchotte; Nantes: Mario Campone, Delphine Loussouarn; Nice: Denys Fontaine, Fanny Vandenbos; Orléans: Claire Blechet, Mélanie Fesneau; Paris: Jean Yves Delattre (national coordinator of the network), Selma Elouadhani-Hamdi, Damien Ricard; Poitiers: Delphine Larrieu-Ciron, Pierre-Marie Levillain; Reims: Philippe Colin, Marie-Danièle Diebold; Rennes: Danchristian Chiforeanu, Elodie Vauléon; Rouen: Olivier Langlois, Annie Laquerrière; Saint-Etienne: Marie Janette Motsuo Fotso, Michel Peoc'h; Saint-Pierre de la réunion: Marie Andraud, Gwenaelle Runavot; Strasbourg: Marie-Pierre Chenard, Georges Noel; Suresnes: Dr Stéphane Gaillard, Dr Chiara Villa; Toulon: Nicolas Desse; Toulouse: Elisabeth Cohen-Moyal, Emmanuelle Uro-Coste; Villejuif: Frédéric Dhermain.

The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3 ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3 . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3 overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3 is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3 recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3 and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3 . A better understanding of spatial and temporal intratumor cell heterogeneity in O3 will open new therapeutic avenues overcoming resistance to current antitumor treatments.
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http://dx.doi.org/10.1111/bpa.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029323PMC
September 2017

Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors.

Neuro Oncol 2017 02;19(2):219-228

Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

Background: Glioblastoma (GBM) is the deadliest primary brain cancer in adults. Emerging innovative therapies hold promise for personalized cancer treatment. Improving therapeutic options depends on research relying on relevant preclinical models. In this line we have established in the setting of the GlioTex project (GBM and Experimental Therapeutics) a GBM patient-derived cell line (GBM-PDCL) library. A multi-omic approach was used to determine the molecular landscape of PDCL and the extent to which they represent GBM tumors.

Methods: Single nucleotide polymorphism array, expression arrays, exome sequencing, and RNA sequencing were used to measure and compare the molecular landscapes of 20 samples representing 10 human GBM tumors and paired GBM-PDCLs.

Results: Copy number variations were similar for a median of 85% of the genome and for 59% of the major focal events. Somatic point mutations were similar in a median of 41%. Mutations in GBM driver and "druggable" genes were maintained in 67% of events. Mutations that were not conserved in the PDCL were mainly low allelic fraction and/or non-driver mutations. Based on RNA expression profiling, PDCLs cluster closely to their parental tumor with overexpression of pathways associated with cancer progression in PDCL.

Conclusions: Overall, PDCLs recapitulate pivotal molecular alterations of paired-parental tumors supporting their use as a preclinical model of GBM. However, some driver aberrations are lost or gained in the passage from tumor to PDCL. Our results support using PDCL as a relevant preclinical model of GBM. Further investigations of changes between PDCLs and their parental tumor may provide insights into GBM biology.
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http://dx.doi.org/10.1093/neuonc/now160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463853PMC
February 2017

Prevalence of IDH1/2 Mutations in Different Subtypes of Glioma in the North-East Population of Morocco.

Asian Pac J Cancer Prev 2016 ;17(5):2649-53

Groupe Hospitalier Pitie-Salpetriere, Laboratoire de Neuropathologie R Escourolle, Paris, France E-mail :

Background: Genetic alterations in gliomas have increasing importance for classification purposes. Thus, we are especially interested in studying IDH mutations which may feature potential roles in diagnosis, prognosis and response to treatment. Our aim was to investigate IDH mutations in diffuse glioma patients diagnosed in university hospital centre of Fez in Morocco.

Materials And Methods: IDH1 codon 132 and IDH2 codon 172 were direct-sequenced in 117 diffuse glioma samples diagnosed and treated in University Hospital Hassan II between 2010 and 2014.

Results: The R132H IDH1 mutation was identified in 43/117 tumor samples and R172K IDH2 mutation was detected in only one anaplastic oligodendroglioma. IDH mutations were observed in 63.2% of astrocytomas, 73.3% of diffuse oligodendrogliomas and 12.90% of glioblastomas.

Conclusions: Our results confirmed other studies published earlier for other populations with some small discrepancies.
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February 2017

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

J Med Genet 2016 08 17;53(8):511-22. Epub 2016 Mar 17.

Svt. Luka's Institute of Child Neurology and Epilepsy, Moscow, Russia.

Objective: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations.

Methods: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.

Results: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15.

Conclusions: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
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http://dx.doi.org/10.1136/jmedgenet-2015-103451DOI Listing
August 2016

Mechanistic signatures of HPV insertions in cervical carcinomas.

NPJ Genom Med 2016 16;1:16004. Epub 2016 Mar 16.

Institut Curie, PSL Research University, Centre National de la Recherche Scientifique UMR3244, Sorbonne Universités, Paris , France.

To identify new personal biomarkers for the improved diagnosis, prognosis and biological follow-up of human papillomavirus (HPV)-associated carcinomas, we developed a generic and comprehensive Capture-HPV method followed by Next Generation Sequencing (NGS). Starting from biopsies or circulating DNA samples, this Capture-NGS approach rapidly identifies the HPV genotype, HPV status (integrated, episomal or absence), the viral-host DNA junctions and the associated genome rearrangements. This analysis of 72 cervical carcinomas identified five HPV signatures. The first two signatures contain two hybrid chromosomal-HPV junctions whose orientations are co-linear (2J-COL) or non-linear (2J-NL), revealing two modes of viral integration associated with chromosomal deletion or amplification events, respectively. The third and fourth signatures exhibit 3-12 hybrid junctions, either clustered in one locus (MJ-CL) or scattered at distinct loci (MJ-SC) while the fifth signature consists of episomal HPV genomes (EPI). Cross analyses between the HPV signatures and the clinical and virological data reveal unexpected biased representation with respect to the HPV genotype, patient age and disease outcome, suggesting functional relevance(s) of this new classification. Overall, our findings establish a facile and comprehensive rational approach for the molecular detection of any HPV-associated carcinoma and definitive personalised sequence information to develop sensitive and specific biomarkers for each patient.
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http://dx.doi.org/10.1038/npjgenmed.2016.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685317PMC
March 2016

Quantifying the heritability of glioma using genome-wide complex trait analysis.

Sci Rep 2015 Dec 2;5:17267. Epub 2015 Dec 2.

Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

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.
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http://dx.doi.org/10.1038/srep17267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667278PMC
December 2015

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas.

Clin Cancer Res 2016 Mar 19;22(5):1185-96. Epub 2015 Oct 19.

Inserm, U 1127, Paris, France. CNRS, UMR 7225, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France. Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital universitaire Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neuropathologie R Escourolle, 47, Bd de l'Hôpital, Paris, France.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842012PMC
March 2016

Differential gene methylation in paired glioblastomas suggests a role of immune response pathways in tumor progression.

J Neurooncol 2015 Sep 30;124(3):385-92. Epub 2015 Jul 30.

Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Hôpital Universitaire la Pitié Salpêtrière, APHP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.

DNA and histone methylation are post-transcriptional modifications that have been recently described in gliomas. Indeed, glioma CpG island hypermethylated phenotype has been identified as prognostic biomarker and as a surrogate marker of IDH1/2 mutations. However, the role of DNA methylation in glioblastoma progression is unknown. We sought to analyze DNA methylation levels in paired (initial and recurrent) primary glioblastoma samples to identify candidate pathways that may prone to glioblastoma progression. We have analyzed 12 samples (5 paired samples, two of them with three surgeries) using methylation arrays. We have analyzed differential methylation at probe and at gene region level. Finally, pathway analysis has been performed using differentially methylated regions. All analysis has been performed with R and Bioconductor packages. Mean methylation level at initial sample compared to recurrence was strongly positively correlated (R(2) = 0.98). There was no differentially methylation at probe level. However, at gene level 3080 regions were differentially methylated. Interestingly, pathways analysis showed that the most differentially methylated genes are involved in cellular response to macrophage colony-stimulating factor stimulus (GO:0036006). Methylation levels were strongly conserved when comparing initial to recurrence in primary glioblastomas. Interestingly, differentially methylated pathway analysis suggests that a modulation of methylation in immune response genes may play a role in glioblastoma progression. Further studies are needed to validate the role of methylation of glioblastoma immune response genes in tumor progression.
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http://dx.doi.org/10.1007/s11060-015-1869-zDOI Listing
September 2015

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

Clin Cancer Res 2015 Jul 21;21(14):3307-17. Epub 2015 Jan 21.

Institute for Cancer Genetics, Columbia University Medical Center, New York, New York. Department of Neurology and Pathology, Columbia University Medical Center, New York, New York.

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. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response.

Results: Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.

Conclusions: RT-PCR sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506218PMC
July 2015

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

J Neurooncol 2015 Feb 7;121(3):499-504. Epub 2014 Dec 7.

UMPC Univ Paris VI, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U 1127, CNRS, UMR 7225; GH Pitié-Salpêtrièr, Sorbonne Universités, 75013, Paris, France.

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. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.
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http://dx.doi.org/10.1007/s11060-014-1677-xDOI Listing
February 2015

DGKI methylation status modulates the prognostic value of MGMT in glioblastoma patients treated with combined radio-chemotherapy with temozolomide.

PLoS One 2014 18;9(9):e104455. Epub 2014 Sep 18.

CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Plate-forme Génomique Santé Biogenouest, Biosit, Rennes, France; Centre Hospitalier Universitaire de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.

Background: Consistently reported prognostic factors for glioblastoma (GBM) are age, extent of surgery, performance status, IDH1 mutational status, and MGMT promoter methylation status. We aimed to integrate biological and clinical prognostic factors into a nomogram intended to predict the survival time of an individual GBM patient treated with a standard regimen. In a previous study we showed that the methylation status of the DGKI promoter identified patients with MGMT-methylated tumors that responded poorly to the standard regimen. We further evaluated the potential prognostic value of DGKI methylation status.

Methods: 399 patients with newly diagnosed GBM and treated with a standard regimen were retrospectively included in this study. Survival modelling was performed on two patient populations: intention-to-treat population of all included patients (population 1) and MGMT-methylated patients (population 2). Cox proportional hazard models were fitted to identify the main prognostic factors. A nomogram was developed for population 1. The prognostic value of DGKI promoter methylation status was evaluated on population 1 and population 2.

Results: The nomogram-based stratification of the cohort identified two risk groups (high/low) with significantly different median survival. We validated the prognostic value of DGKI methylation status for MGMT-methylated patients. We also demonstrated that the DGKI methylation status identified 22% of poorly responding patients in the low-risk group defined by the nomogram.

Conclusions: Our results improve the conventional MGMT stratification of GBM patients receiving standard treatment. These results could help the interpretation of published or ongoing clinical trial outcomes and refine patient recruitment in the future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104455PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169423PMC
June 2015

Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients.

Neurobiol Aging 2014 Dec 18;35(12):2882.e13-2882.e15. Epub 2014 Jul 18.

Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR 7225, Inserm U 1127, Sorbonne Universités, Université Pierre et Marie, Univ Paris 06, UPMC-P6 UMR S 1127 - Hôpital Pitié-Salpêtrière, Paris, France; Centre de Référence des Démences Rares, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; Département de Neurologie, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are adult-onset neurodegenerative diseases with overlapping clinical characteristics. They share common genetic causes and pathologic hallmarks such as TDP-43 neuronal accumulations. Recently, exome analysis identified mutations in matrin 3 (MATR3) gene in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease. MATR3 is a nuclear matrix protein with DNA and RNA binding domains that interacts with TDP-43. To confirm the contribution of MATR3 to ALS, we studied a French cohort of 153 familial ALS or ALS/FTLD patients, without finding any variant. We conclude that mutations in MATR3 are rare in French familial ALS and ALS with FTLD patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.016DOI Listing
December 2014

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

Neurology 2014 Sep 22;83(13):1200-6. Epub 2014 Aug 22.

From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.

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.
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http://dx.doi.org/10.1212/WNL.0000000000000814DOI Listing
September 2014

Diagnostic and prognostic value of preoperative combined GFAP, IGFBP-2, and YKL-40 plasma levels in patients with glioblastoma.

Cancer 2014 Dec 19;120(24):3972-80. Epub 2014 Aug 19.

Neurology Service 2, Mazarin Division, Pitié-Salpêtrière Hospital, AP-HP; Sorbonne Universités, UPMC Univ Paris 06, UM 75; CNRS, UMR 7225; Inserm, U1127; ICM, F-75013, Paris, France; Department of Neurology, Clinic of the University of Navarra, University of Navarra School of Medicine, Pamplona, Spain.

Background: Circulating proteins released by tumor cells have recently been investigated as potential single surrogate biomarkers for glioblastoma multiforme (GBM). The aim of the current hypothesis-generating study was to evaluate the diagnostic and prognostic role of preoperative insulin-like growth factor-binding protein 2 (IGFBP-2), chitinase-3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) plasma levels in patients with GBM, both as single markers and as a combined profile.

Methods: Plasma samples from 111 patients with GBM and a subset of 40 patients with nonglial brain tumors were obtained preoperatively. Plasma from 99 healthy controls was also analyzed. IGFBP-2, YKL-40, and GFAP levels were determined using enzyme-linked immunoadsorbent assay tests. Their association with histological and radiological variables was assessed.

Results: Circulating levels of all 3 proteins were found to be significantly higher in patients with GBM compared with healthy controls (P < .01). Only YKL-40 and GFAP were found to demonstrate significant differences between patients with GBM and nonglial brain tumors (P = .04). GFAP was undetectable (<0.02 ng/mL) in all patients without GBM. A receiver operating characteristic analysis accounting for a 2-step diagnostic procedure including the 3 biomarkers afforded an area under the curve of 0.77 for differentiating patients with GBM from those with nonglial brain tumors. There was a significant correlation between tumor volume and plasma IGFBP-2 level (Spearman Rho correlation coefficient, 0.22; P = .025) and GFAP (Spearman Rho correlation coefficient, 0.36; P < .001) among patients with GBM. Preoperative plasma IGFBP-2 levels were found to be independently associated with worse overall survival among patients with GBM (hazard ratio, 1.3; P = .05).

Conclusions: A combined profile of preoperative IGFBP-2, GFAP, and YKL-40 plasma levels could serve as an additional diagnostic tool for patients with inoperable brain lesions suggestive of GBM. In addition, IGFBP-2 levels appear to constitute an independent prognostic factor in patients with GBM.
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http://dx.doi.org/10.1002/cncr.28949DOI Listing
December 2014
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