Publications by authors named "Marine Giry"

19 Publications

  • Page 1 of 1

Quantitative brain imaging analysis of neurological syndromes associated with anti-GAD antibodies.

Neuroimage Clin 2021 Sep 20;32:102826. Epub 2021 Sep 20.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neurology 2 Department Mazarin, F-75013 Paris, France; Sorbonne Université, Inserm, CNRS, Paris Brain Institute, Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France. Electronic address:

Neurological disorders associated with anti-glutamic acid decarboxylase (GAD) autoimmunity are rare and include a variety of neurological syndromes: stiff-person syndrome, cerebellar ataxia or limbic encephalitis. The diagnosis remains challenging due to the variety of symptoms and normal brain imaging. The morphological MRI of 26 patients (T1-weighted and Fluid-attenuated inversion recovery (FLAIR)-weighted images) was analyzed at the initial stage of diagnosis, matched by age and sex to 26 healthy subjects. We performed a vertex-wise analysis using a generalized linear model, adjusting by age, to compare the brain cortical thickness of both populations. In addition, we used a voxel-based morphometry of cerebellum thickness obtained by CEREbellum Segmentation (CERES), as well as the hippocampus volumetry comparison using HIPpocampus subfield Segmentation (HIPS). Finally, we extracted 62 radiomics features using LifeX to assess the classification performance using a random forest model to identify an anti-GAD related MRI. The results suggest a peculiar profile of atrophy in patients with anti-GAD, with a significant atrophy in the temporal and frontal lobes (adjusted p-value < 0.05), and a focal cerebellar atrophy of the V-lobule, independently of the anti-GAD phenotype. Finally, the MRIs from anti-GAD patients were correctly classified when compared to the control group, with an area under the curve (AUC) of 0.98. This study suggests a particular pattern of cortical atrophy throughout all anti-GAD phenotypes. These results reinforce the notion that the different neurological anti-GAD phenotypes should be considered as a continuum due to their similar cortical thickness profiles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2021.102826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476448PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168809PMC
June 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clineuro.2020.106006DOI Listing
September 2020

Neurological Syndromes Associated with Anti-GAD Antibodies.

Int J Mol Sci 2020 May 24;21(10). Epub 2020 May 24.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, service de Neurologie 2-Mazarin, 75013 Paris, France.

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21103701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279468PMC
May 2020

Mechanisms and therapeutic implications of hypermutation in gliomas.

Nature 2020 04 15;580(7804):517-523. Epub 2020 Apr 15.

Drug Development Department (DITEP), INSERM U1015, Université Paris Saclay, Gustave Roussy, Villejuif, France.

A high tumour mutational burden (hypermutation) is observed in some gliomas; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235024PMC
April 2020

Actionable FGFR1 and BRAF mutations in adult circumscribed gliomas.

J Neurooncol 2019 Nov 31;145(2):241-245. Epub 2019 Oct 31.

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, 75013, Paris, France.

Purpose: Circumscribed gliomas -pilocytic astrocytomas (PA), gangliogliomas (GG), ependymomas (EP)- are mostly low-grade tumours but may progress to anaplasia and sometimes surgery can be challenging due to deep anatomical localization. Because of the high frequency of MAPK-pathway alterations and availability of targeted therapies for FGFR1 and BRAF-mutated tumors, we investigated these mutational hotspots in a cohort of adult circumscribed gliomas.

Methods: Adult patients (>15 years) with diagnosis of PA, GG, EP and DNET were retrospectively identified from two institutions databases. Genomic DNA was extracted from formalin-fixed paraffin-embedded or frozen samples and exons including codons 546 and 656 of FGFR1 and V600 of BRAF were sequenced.

Results: FGFR1 mutations were identified in 15/108 PA and were particularly frequent in optic pathway (6/9 vs. 9/108; p = 10). FGFR1 was mutated in 3/75 grade II versus 2/7 grade III GG (p = 0.05), 1/7 DNET, 1/100 EP grade II. We found 3/108 PA with BRAF pVal600Glu and 6/108 with p.Thr599_Val600insThr. The p.Val600Glu was found in 14/75 grade II GG. No EP were BRAF mutated.

Conclusions: We report actionable targets, including frequent FGFR1 mutation in optic-pathway PA that makes them excellent candidates to anti-FGFR therapies, and BRAF non-canonical mutations in PA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-019-03306-9DOI Listing
November 2019

Neuropathic pain, dysautonomia, and nerve hyperexcitability: Expanding the spectrum of LGI1 autoimmunity.

Clin Neurophysiol 2019 02 7;130(2):248-250. Epub 2018 Dec 7.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975, Paris 75013, France; Inserm U 975, CNRS, UMR 7225, Paris 75013, France; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2018.11.017DOI Listing
February 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04622-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006150PMC
June 2018

Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies.

Br J Cancer 2018 07 14;119(1):105-113. Epub 2018 Jun 14.

Brain and Spine Institute (ICM), Experimental Neuro-Oncology Department, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, 75013, Paris, France.

Background: Paraneoplastic neurological syndromes are rare conditions where an autoimmune reaction against the nervous system appears in patients suffering from a tumour, but not linked to the spreading of the tumour. A break in the immune tolerance is thought to be the trigger.

Methods: The transcriptomic profile of 12 ovarian tumours (OT) from patients suffering from paraneoplastic cerebellar degeneration (PCD) linked to anti-Yo antibodies (anti-Yo PCD OT) was compared with 733 ovarian tumours (OT control) from different public databases using linear model analysis.

Results: A prominent significant transcriptomic over-representation of CD8+ and Treg cells was found in anti-Yo PCD OT, as compared to the OT control. However, the overall degree of immune cell infiltration was similar, according to the ESTIMATE immune score. We also found an under-representation of M2 macrophages in anti-Yo PCD OT. Furthermore, the differentially expressed genes were enriched for AIRE-related genes, a well-known transcription factor associated with a broad range of autoimmune diseases. Finally, we found that the differentially expressed genes were correlated to the transcriptomic profiling of the cerebellar structures.

Conclusions: Our data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0125-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035206PMC
July 2018

De novo and secondary anaplastic meningiomas: a study of clinical and histomolecular prognostic factors.

Neuro Oncol 2018 07;20(8):1113-1121

Department of Neurosurgery, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France.

Background: Following recent studies underlining the differences between de novo and secondary anaplastic meningiomas and the prognostic value of telomerase reverse transcriptase (TERT) promoter mutation, we decided to conduct a multicenter retrospective study to address these questions and determine specific prognostic factors in each of these 2 anaplastic meningioma subgroups.

Methods: Among the 68 meningioma cases initially selected, only 57 were confirmed as anaplastic meningiomas after centralized pathological review. TERT promoter mutation analysis was performed in all cases.

Results: Median overall survival was 2.6 years and 5-year survival rate was 10%. This study confirmed the better prognosis of de novo anaplastic meningiomas (28 tumors) compared with secondary anaplastic meningiomas (29 tumors) (P = 0.02). In the "de novo" group, meningiomas diagnosed on histological anaplasia alone had a better prognosis than those in patients with a high number of mitoses with or without anaplasia (P = 0.01). In the "secondary" group, tumors demonstrate very heterogeneous clinical courses leading to malignant transformation, and time to first relapse as a low-grade tumor was a strong predictor of overall survival (P = 0.0007). TERT promoter mutation in anaplastic meningiomas was rare (14%) and did not influence overall survival but was associated with a shorter recurrence-free survival in the secondary anaplastic meningioma subgroup (P = 0.02). The absence of TERT promoter methylation, although rare (3/33 cases), may be associated with prolonged overall survival (P = 0.02).

Conclusion: This study highlights the different prognoses of de novo and secondary anaplastic meningiomas with specific prognostic factors in each subgroup. The analysis of TERT mutation and methylation could provide additional prognostic insights.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nox231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280137PMC
July 2018

Diffuse gliomas with FGFR3-TACC3 fusion have characteristic histopathological and molecular features.

Brain Pathol 2018 09 21;28(5):674-683. Epub 2017 Nov 21.

AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Service de Neuropathologie Raymond Escourolle, Paris, France.

Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n = 27 WHO grade IV and n = 3 WHO grade II) as well as their histological and molecular features. We observed recurrent morphological features (monomorphous ovoid nuclei, nuclear palisading and thin parallel cytoplasmic processes, endocrinoid network of thin capillaries) associated with frequent microcalcifications and desmoplasia. We report a constant immunoreactivity for FGFR3, which is a valuable method for screening for the FGFR3-TACC3 fusion with 100% sensitivity and 92% specificity. We confirmed the associated molecular features (typical genetic alterations of glioblastoma, except the absence of EGFR amplification, and an increased frequency of CDK4 and MDM2 amplifications). FGFR3 immunopositivity is a valuable tool to identify gliomas that are likely to harbor the FGFR3-TACC3 fusion for inclusion in targeted therapeutic trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028622PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/8045859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530437PMC
April 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029323PMC
September 2017

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

Oncologist 2016 09 8;21(9):1131-5. Epub 2016 Jul 8.

Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, Paris, France INSERM U1127, Paris, France Centre National de la Recherche Scientifique, Unité de Recherche Mixte 7225, Paris, France OncoNeuroTek, Paris, France Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2016-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016064PMC
September 2016

TERT promoter mutations and rs2853669 polymorphism: prognostic impact and interactions with common alterations in glioblastomas.

J Neurooncol 2016 Feb 25;126(3):441-6. Epub 2015 Nov 25.

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

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-015-1999-3DOI Listing
February 2016

Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis.

Am J Surg Pathol 2015 Jul;39(7):948-56

*Neuropathology Department Raymond-Escourolle ***AP-HP, Neurology 2 Mazarin Department, Pitié-Salpêtrière Hospital §§§Onconeurotek, Pitié-Salpêtrière Hospital ††Pathology Department, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris †Sorbonne Universités, UPMC Univ Paris 06, UM 75 ‡Institut National de la Santé et de la Recherche Médicale, U 1127 §Centre National de la Recherche Scientifique, UMR 7225, ICM ∥Brain and Spine Institute #Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Université Paris Descartes, Paris ¶Department of Anatomical and Cytological Pathology, Hôpital Foch, Suresnes **Pathology Department, Hôpital Bretonneau, CHRU Tours, Tours ‡‡Pathology and Neuropathology Department, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron §§Pathology Department, Plateau technique de Biologie, CHU, Dijon ∥∥Department of Pathology, Caen University Hospital ¶¶Centre National de la Recherche Scientifique, UMR 6301 ISTCT CERVOxy Group, Caen ##Pathology Department, CHU Besançon, Besançon †††Pathology and Neuropathology Department, Assistance Publique-Hôpitaux de Marseille, AP-HM CHU, Timone ‡‡‡Aix-Marseille university, INSERM U911, Marseille, France.

Chordoid glioma of the third ventricle (CG3V) is a rare tumor developing in a stereotyped localization. It has been related to the circumventricular organ of the lamina terminalis, in the anterior part of the third ventricle, but its oncogenesis is poorly understood. TTF-1 transcription factor is involved in the development and adult physiology of the ventral forebrain. We studied the histopathologic and immunohistochemical features of a multicentric series of 17 cases of CG3V. We described additional histologic patterns (solid, fibrosing, and fusiform) to the typical chordoid pattern. TTF-1 was constantly expressed in CG3V, as in developing and adult lamina terminalis. The anti-TTF-1 SPT24 clone was more sensitive than the 8G7G3/1 clone. No mutation of IDH1 R132, IDH2 R172, or BRAF V600 codons was found. We showed TTF-1 as a useful marker for the diagnosis of CG3V and the understanding of its oncogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000421DOI Listing
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-14-2199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506218PMC
July 2015

Molecular analysis of diffuse intrinsic brainstem gliomas in adults.

J Neurooncol 2014 Jan 17;116(2):405-11. Epub 2013 Nov 17.

Service de Neurologie 2, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-013-1312-2DOI Listing
January 2014

Prevalence, clinico-pathological value, and co-occurrence of PDGFRA abnormalities in diffuse gliomas.

Neuro Oncol 2012 Nov 16;14(11):1393-403. Epub 2012 Oct 16.

CRICM, INSERM UMRS 975/CNRS UMR 7225/UPMC, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Neurology2-Mazarin, Paris, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nos217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480267PMC
November 2012
-->