ABSTRACT
A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; 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.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/therapy , Glioma/genetics , Glioma/therapy , Mutation , Animals , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/immunology , DNA Mismatch Repair/genetics , Gene Frequency , Genome, Human/drug effects , Genome, Human/genetics , Glioma/immunology , Humans , Male , Mice , Microsatellite Repeats/drug effects , Microsatellite Repeats/genetics , Mutagenesis/drug effects , Mutation/drug effects , Phenotype , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Sequence Analysis, DNA , Temozolomide/pharmacology , Temozolomide/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.
ABSTRACT
BACKGROUND AND PURPOSE: Despite their detrimental impact on the quality of life in autoimmune encephalitis, sleep disorders have not been investigated in anti-glutamic acid decarboxylase (GAD65) associated neurological syndromes. METHODS: Six consecutive adult patients diagnosed with anti-GAD65-associated neurological syndromes (four with limbic encephalitis and two with stiff-person syndrome) and 12 healthy controls were enrolled. Participants underwent sleep interviews and sleep studies including night-time video-polysomnography, followed by five daytime multiple sleep latency tests (MSLTs, to assess propensity to fall asleep) and an 18 h bed rest polysomnography (to assess excessive sleep need). RESULTS: Patients reported the need for daily naps and that their cognition and quality of life were altered by sleepiness, but they had normal scores on the Epworth sleepiness scale. Compared with controls, sleep latencies during the MSLT were shorter in the patient group (median 5.8 min, interquartile range [IQR] 4.5, 6.0 vs. 17.7 min, IQR 16.3, 19.7, p = 0.001), and the arousal index was reduced (2.5/h, IQR 2.3, 3.0 vs. 22.3/h, IQR 13.8, 30.0, p = 0.002), although total sleep time was similar between groups (621 min, IQR 464, 651 vs. 542.5 min, IQR 499, 582, p = 0.51). Remarkably, all six patients had MSLT latencies ≤8 min, indicating severe sleepiness. No parasomnia or sleep-disordered breathing was detected. CONCLUSION: Central hypersomnia is a relevant characteristic of anti-GAD65-associated neurological syndromes.
Subject(s)
Carboxy-Lyases , Disorders of Excessive Somnolence , Adult , Humans , Pilot Projects , Sleepiness , Quality of Life , Disorders of Excessive Somnolence/etiology , Disorders of Excessive Somnolence/diagnosisABSTRACT
The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.
Subject(s)
Central Nervous System Neoplasms , Immunotherapy, Adoptive , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Male , Female , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/mortality , Middle Aged , Aged , Retrospective Studies , Leukapheresis , Remission Induction , Adult , Aged, 80 and over , Receptors, Chimeric AntigenABSTRACT
BACKGROUND: Strategies to modulate the tumor microenvironment (TME) have opened new therapeutic avenues with dramatic yet heterogeneous intertumoral efficacy in multiple cancers, including glioblastomas (GBMs). Therefore, investigating molecular actors of TME may help understand the interactions between tumor cells and TME. Immune checkpoint proteins such as a Cluster of Differentiation 80 (CD80) and CD86 are expressed on the surface of tumor cells and infiltrative tumor lymphocytes. However, their expression and prognostic value in GBM microenvironment are still unclear. METHODS: In this study, we investigated, in a retrospective local discovery cohort and a validation TCGA dataset, expression of CD80 and CD86 at mRNA level and their prognostic significance in response to standard of care. Furthermore, CD80 and CD86 at the protein level were investigated in the discovery cohort. RESULTS: Both CD80 and CD86 are expressed heterogeneously in the TME at mRNA and protein levels. In a univariate analysis, the mRNA expression of CD80 and CD86 was not significantly correlated with OS in both local OncoNeuroTek dataset and TCGA datasets. CD80 and CD86 mRNA high expression was significantly associated with shorter progression free survival (PFS) (p < 0.05). These findings were validated using the TCGA cohort; higher CD80 and CD86 expressions were correlated with shorter PFS (p < 0.05). In multivariate analysis, CD86 mRNA expression was an independent prognostic factor for PFS in the TCGA dataset only (p < 0.05). CONCLUSION: CD86 could be used as a potential biomarker for the prognosis of GBM patients treated with immunotherapy; however, additional studies are needed to validate these findings.
Subject(s)
Glioblastoma , Humans , Prognosis , Glioblastoma/diagnosis , Glioblastoma/genetics , Retrospective Studies , Tumor Microenvironment , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) located in the CNS with a less favorable prognosis. Recent information addressing the disease molecular heterogeneity is paving the way for tailored treatment strategies. This article reviews current work on the pathogenesis of the disease, potential biomarkers, and treatments. RECENT FINDINGS: Previous molecular classifications of PCNSL, built on DLBCL heterogeneity, did not properly address its intrinsic variability. Recent evidence has shown the existence of four different molecular PCNSL subtypes with associated multiomic characteristics, including prognostic relevance. Several studies have identified the tumor microenvironment (TME) as a driving prognostic factor in PCNSL. Therapy efforts continue mainly into targeting either the NF-κß (nuclear factor kappa-light-chain enhancer of activated B cells) pathway or modulating the TME through immunomodulatory drugs (lenalidomide) or immunotherapy (antiprogrammed cell death 1/programmed cell death 1 ligand 1). SUMMARY: Despite the increasing understanding of PCNSL pathogenesis with recent studies, future efforts are still needed to yield diagnostic biomarkers to detect either PCNSL or its molecular subtypes and hence ease routine clinical use.
Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Humans , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Prognosis , Biomarkers , Central Nervous System/pathology , Tumor MicroenvironmentABSTRACT
PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal diffuse large B cell lymphoma. Despite its apparent immunopathological homogeneity, PCNSL displays a wide variability in outcome. Identifying prognostic factors is of importance for patient stratification and clinical decision-making. The purpose of this review is to focus on the clinical, neuroradiological and biological variables correlated with the prognosis at the time of diagnosis in immunocompetent patients. RECENT FINDINGS: Age and performance status remain the most consistent clinical prognostic factors. The current literature suggests that neurocognitive dysfunction is an independent predictor of poor outcome. Cumulating data support the prognostic value of increased interleukin-10 level in the cerebrospinal fluid (CSF), in addition to its interest as a diagnostic biomarker. Advances in neuroimaging and in omics have identified several semi-quantitative radiological features (apparent diffusion restriction measures, dynamic contrast-enhanced perfusion MRI (pMRI) pattern and 18F-fluorodeoxyglucose metabolism) and molecular genetic alterations with prognostic impact in PCNSL. SUMMARY: Validation of new biologic and neuroimaging markers in prospective studies is required before integrating future prognostic scoring systems. In the era of radiomic, large clinicoradiological and molecular databases are needed to develop multimodal artificial intelligence algorithms for the prediction of accurate outcome.
Subject(s)
Biological Products , Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Artificial Intelligence , Biomarkers , Central Nervous System/pathology , Central Nervous System Neoplasms/diagnostic imaging , Fluorodeoxyglucose F18 , Humans , Interleukin-10/cerebrospinal fluid , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/genetics , PrognosisABSTRACT
Most relapses of primary central nervous system lymphoma (PCNSL) occur in the brain and are associated with a poor prognosis. Isolated intraocular relapses (IIORs) are rare and poorly described. We retrospectively selected from the French Lymphome Oculo-Cérébral database PCNSL patients who initially presented with cerebral localization and who experienced IIOR during the course of the disease. Of the 1472 patients included in the database, 55 patients presented an IIOR. Their median age was 68 years, and median Karnofsky Performance Status 80. IL-10 levels in the aqueous humor and/or in the vitreous were increased in 42/46 patients. 45/55 patients received systemic chemotherapy, and 11/55 received high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) as consolidation treatment. After a median follow-up of 69 months, 42/55 patients had relapsed, including 90% of the patients who did not receive HCT-ASCT at IIOR and 40% of the patients who received HCT-ASCT at IIOR (p < 0.001). The first relapse after the initial IIOR was exclusively in the eye in 23/42 patients, and 29/42 patients had a subsequent brain relapse during the course of the disease. The median progression-free survival, brain-free survival and overall survival from IIOR were 12.2, 48.6 and 57.1 months, respectively. Isolated intraocular relapse is not exceptional in the course of PCNSL and deserves systematic ophthalmological follow-up. Its prognosis is much better than the prognosis of brain relapse, with an evolution close to that of primary vitreoretinal lymphoma. With the exception of patients who received HCT-ASCT at IIOR, almost all patients subsequently relapsed, often with other IIORs.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma , Retinal Neoplasms , Humans , Aged , Transplantation, Autologous , Retrospective Studies , Vitreous BodyABSTRACT
INTRODUCTION: The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSLs). In this cohort study, we described the neurocognition of patients with PCNSL-CC and its posttherapeutic evolution. METHODS: Immunocompetent patients with PCNSL-CC were identified retrospectively at the Pitié-Salpêtrière Hospital. We described their clinical presentation. Neuropsychological test scores (MMSE; digit spans; Free and Cued Selective Reminding Test; Image Oral Naming Test; Frontal Assessment Battery; Trail Making Test; Stroop and verbal fluency tests; Rey's Complex Figure test) and factors impacting them were analyzed. RESULTS: Twenty-seven patients were included (median age: 67 years, median Karnofsky Performance Status: 70); cognitive impairment and balance disorders were present in 74% and 59%, respectively. At diagnosis, neuropsychological test results were abnormal for global cognitive efficiency (63% of patients), memory (33-80% depending on the test) and executive functions (44-100%). Results for visuospatial and language tests were normal. All patients received high-dose methotrexate-based polychemotherapy, followed in one patient by whole-brain radiotherapy; 67% of patients achieved complete response (CR). With a median follow-up of 48 months (range 6-156), patients in CR had persistent abnormal test results for global cognitive efficiency in 17%, executive function in 18-60%, depending on the test, and memory in 40-60%. Splenium location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up. CONCLUSIONS: PCNSL-CC is associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR and warrant specific rehabilitation. Older age (≥ 60) and splenium location are associated with worse neurocognitive outcomes.
Subject(s)
Corpus Callosum , Lymphoma , Aged , Cohort Studies , Corpus Callosum/diagnostic imaging , Corpus Callosum/pathology , Humans , Lymphoma/drug therapy , Lymphoma/therapy , Middle Aged , Neuropsychological Tests , Retrospective StudiesABSTRACT
Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, we evaluated the antiproliferative activity by wst-1 assay of six ferrocifens in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC50) values varied significantly (10 nM < IC50 < 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC50 = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM.
Subject(s)
Biomarkers, Tumor/biosynthesis , Ferrous Compounds/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma , Tamoxifen/pharmacology , Transcriptome/drug effects , Cell Line, Tumor , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Structure-Activity RelationshipABSTRACT
B-cell non-Hodgkin's lymphoma (NHL) risk associations had been mainly attributed to family history of the disease, inflammation, and immune components including human leukocyte antigen (HLA) genetic variations. Nevertheless, a broad range of genome-wide association studies (GWAS) have shed light into the identification of several genetic variants presumptively associated with B-cell NHL etiologies, survival or shared genetic risk with other diseases. The present review aims to overview HLA structure and diversity and summarize the evidence of genetic variations, by GWAS, on five NHL subtypes (diffuse large B-cell lymphoma DLBCL, follicular lymphoma FL, chronic lymphocytic leukemia CLL, marginal zone lymphoma MZL, and primary central nervous system lymphoma PCNSL). Evidence indicates that the HLA zygosity status in B-cell NHL might promote immune escape and that genome-wide significance variants can give biological insight but also potential therapeutic markers such as WEE1 in DLBCL. However, additional studies are needed, especially for non-DLBCL, to replicate the associations found to date.
Subject(s)
Central Nervous System Neoplasms/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Lymphoma, Follicular/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Non-Hodgkin/genetics , Genetic Background , HLA Antigens/metabolism , Humans , Lipids/chemistry , Risk , Risk FactorsABSTRACT
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.
Subject(s)
Autoimmune Diseases of the Nervous System/immunology , Autoimmunity , Glutamate Decarboxylase/immunology , Neurons/enzymology , Autoimmune Diseases of the Nervous System/diagnosis , Autoimmune Diseases of the Nervous System/therapy , Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/immunology , Cerebellar Ataxia/therapy , Humans , Limbic Encephalitis/diagnosis , Limbic Encephalitis/immunology , Limbic Encephalitis/therapy , Neurons/immunology , Stiff-Person Syndrome/diagnosis , Stiff-Person Syndrome/immunology , Stiff-Person Syndrome/therapyABSTRACT
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal lymphoma. Despite established clinical prognostic scoring such as that of the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Extranodal Lymphoma Study Group, outcome prediction needs to be improved. Several studies have indicated an association between changes in hematologic laboratory parameters with patient outcomes in PCNSL. We sought to assess the association between hematological parameters and overall survival (OS) in patients with PCNSL. METHODS: Pretreatment blood tests were analyzed in patients with newly diagnosed PCNSL (n = 182), and we divided the analysis into two cohorts (A and B, both n = 91). OS was evaluated using the Cox proportional hazards models and log-rank test. Furthermore, the accuracy of the different multivariate models was assessed by Harrell's concordance index (C-index). RESULTS: Using prechemotherapy blood tests, anemia was found in 38 patients (41.8%) in cohort A and 34 patients (37.4%) in cohort B. In univariate analysis, anemia (<12 g/dL in women and <13 g/dL in men) was significantly associated with OS. None of the other blood tests parameters (neutrophils, lymphocyte, or platelets counts) or their ratios (neutrophil-to-lymphocyte ratio and neutrophil-to-platelets ratio) were associated with OS. In multivariate analysis, after adjusting by MSKCC score, anemia remained an independent prognostic factor. Interestingly, the prediction accuracy of OS using Harrell's C-index was similar using anemia or MSKCC (mean C-index, 0.6) and was increased to 0.67 when combining anemia and MSKCC. CONCLUSION: The presence of anemia was associated with poor prognosis in both cohorts of PCNSL. Validation of these results and biologic role of hemoglobin levels in PCNSL requires further investigation. IMPLICATIONS FOR PRACTICE: The prediction of the outcome of primary central nervous system lymphoma (PCNSL) using the most frequently used scores (i.e., Memorial Sloan Kettering Cancer Center [MSKCC] or International Extranodal Lymphoma Study Group) needs to be improved. We analyzed a large cohort of PCNSL to dissect the potential prognostic value of blood tests in this rare entity. We found anemia as an independent predictor for overall survival in PCNSL. Interestingly, the accuracy to predict PCNSL outcome was improved using hemoglobin level. This improvement was additional to the currently used clinical score (i.e., MSKCC). Finally, none of the other blood tests parameters or their ratios had a prognostic impact in this study.
Subject(s)
Anemia/blood , Central Nervous System Neoplasms/blood , Hemoglobins/metabolism , Prognosis , Aged , Blood Platelets/metabolism , Blood Platelets/pathology , Central Nervous System Neoplasms/epidemiology , Central Nervous System Neoplasms/pathology , Disease-Free Survival , Female , Humans , Lymphocytes/pathology , Male , Middle Aged , Nervous System/metabolism , Nervous System/pathology , Neutrophils/pathology , Proportional Hazards ModelsABSTRACT
Primary CNS lymphomas (PCNSL) are rare and poor prognosis diffuse large B-cell lymphomas. Because of the brain tumor environment and the restricted distribution of drugs in the CNS, specific PCNSL patient-derived orthotopic xenograft (PDOX) models are needed for preclinical research to improve the prognosis of PCNSL patients. PCNSL patient specimens (nâ¯=â¯6) were grafted in the caudate nucleus of immunodeficient nude mice with a 83% rate of success, while subcutaneous implantation in nude mice of human PCNSL sample did not generate lymphoma, supporting the role of the brain microenvironment in the PCNSL physiopathology. PDOXs showed diffuse infiltration of B-cell lymphoma cells in the brain parenchyma. Each model had a unique mutational signature for genes in the BCR and NF-κB pathways and retained the mutational profile of the primary tumor. The models can be stored as cryopreserved biobank. Human IL-10 levels measured in the plasma of PCNSL-PDOX mice showed to be a reliable tool to monitor the tumor burden. Treatment response could be measured after a short treatment with the targeted therapy ibrutinib. In summary, we established a panel of human PCNSL-PDOX models that capture the histological and molecular characteristics of the disease and that proved suitable for preclinical experiments. Our methods of generation and characterization will enable the generation of additional PDOX-PCNSL models, essential tools for cognitive and preclinical drug discovery.
Subject(s)
Central Nervous System Neoplasms/pathology , Disease Models, Animal , Heterografts/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Adenine/analogs & derivatives , Animals , Caudate Nucleus , Heterografts/drug effects , Humans , Interleukin-10/analysis , Mice , Mice, Nude , Piperidines , Prognosis , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Tumor BurdenABSTRACT
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.
Subject(s)
Nerve Tissue Proteins/genetics , Ovarian Neoplasms/genetics , Paraneoplastic Cerebellar Degeneration/genetics , Transcriptome/genetics , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Microarray Analysis , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Nerve Tissue Proteins/immunology , Ovarian Neoplasms/complications , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Paraneoplastic Cerebellar Degeneration/complications , Paraneoplastic Cerebellar Degeneration/immunology , Paraneoplastic Cerebellar Degeneration/pathology , T-Lymphocytes, Regulatory/immunology , Transcription Factors/genetics , Transcription Factors/immunology , Transcriptome/immunology , AIRE ProteinABSTRACT
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: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT 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.
Subject(s)
DNA Copy Number Variations/genetics , Machine Learning/standards , Oligodendroglioma/genetics , Cohort Studies , Female , Humans , Male , Middle Aged , Oligodendroglioma/mortality , Oligodendroglioma/pathology , PrognosisABSTRACT
INTRODUCTION: There is currently no treatment for solitary fibrous tumors/hemangiopericytomas (SFT/H) of the central nervous system recurring after multiple surgeries and radiotherapies. The NAB2-STAT6 gene fusion is the hallmark of these tumors, and upregulates Early Growth Factor, activating several growth pathways. METHODS: We treated two patients presenting pluri-recurrent meningeal SFT/H with Pazopanib, a broad-spectrum tyrosine kinase inhibitor. We analyzed the exome and RNA sequencing data of one of them and, in addition to another meningeal SFT/H, compared it to the transcriptomic profiling of 5 systemic SFT/H. RESULTS: A dramatic clinical and radiological response was observed in both cases, respectively 84 and 43% decrease after 3 months. As a comparison, Pazopanib has only a stabilizing effect in systemic SFT/H. Indeed, central nervous system SFT/H show overexpression of different tyrosine kinases targeted by Pazopanib. CONCLUSIONS: Two consecutive patients with untreatable central nervous system SFT/H showed a spectacular partial response to Pazopanib, an unprecedented result in SFT/H. This result could be explained by differences in expression profiles and calls for a confirmation in a larger cohort of patients.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Central Nervous System Neoplasms/drug therapy , Hemangiopericytoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Pyrimidines/therapeutic use , Solitary Fibrous Tumors/drug therapy , Sulfonamides/therapeutic use , Adult , Central Nervous System Neoplasms/diagnostic imaging , Central Nervous System Neoplasms/metabolism , Female , Hemangiopericytoma/diagnostic imaging , Hemangiopericytoma/metabolism , Humans , Indazoles , Male , Middle Aged , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/metabolism , Solitary Fibrous Tumors/diagnostic imaging , Solitary Fibrous Tumors/metabolism , Treatment OutcomeABSTRACT
PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare cancer with a somber prognosis in older patients, which it affects predominantly. Only in recent years have molecular alterations characterizing PCNSL been thoroughly described. This opens possibilities for the use of targeted therapies. Developments in imaging and biomarkers have also great potential to help clinicians faced with diagnostic and prognostic uncertainties. RECENT FINDINGS: Several biomarkers for PCNSL, such as different microRNAs, which could be tested in cerebrospinal fluid and vitreous fluid, and IL-10, which has been shown to have excellent sensitivity and specificity in the cerebrospinal fluid, have emerged in the last years. Methotrexate-based regimens remain the gold standard first-line treatment, with recent studies looking at the best adjunctive molecules to methotrexate, including rituximab, and at the role of autologous stem cell transplantation. As mutations leading to the activation of nuclear factor-kappa-B signaling are found in most PCNSLs, with mutations of MYD88 and CD79B particularly, ibrutinib is studied as molecule of great interest and encouraging results have been found in pilot studies. There is also great interest in the immunomodulatory drugs (lenalidomide) and immunotherapy (anti-programmed cell death 1/programmed cell death 1 ligand 1). SUMMARY: Identification of molecular genetic and cytokine changes in tumor and liquid biopsies will have an increasing role in the diagnostic and follow-up of PCNSL but also in the treatment and management of the disease.
Subject(s)
Biological Therapy/methods , Biomarkers , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/therapy , Lymphoma/diagnosis , Lymphoma/therapy , HumansABSTRACT
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.
Subject(s)
Glioma/genetics , Isocitrate Dehydrogenase/genetics , Loss of Heterozygosity/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Biomarkers, Tumor/genetics , Chromosomes, Human, Pair 17/genetics , Disease-Free Survival , Female , Glioma/epidemiology , Glioma/pathology , Humans , Male , Middle Aged , Mutation , PrognosisABSTRACT
OBJECTIVE: CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood. METHODS: We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expression of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1(R132H) cells transfected with lentivirus encoding mutant and WT CIC. RESULTS: We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p = 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation of normally CIC repressed genes ETV1, ETV4, ETV5, and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1(R132H) and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1. INTERPRETATION: CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma.