Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

Glial Cell Adhesion Molecule (GlialCAM) Determines Proliferative versus Invasive Cell States in Glioblastoma.

The malignant brain cancer glioblastoma (GBM) contains groups of highly invasive cells that drive tumor progression as well as recurrence after surgery and chemotherapy. The molecular mechanisms that enable these GBM cells to exit the primary mass and disperse throughout the brain remain largely unknown. Here we report using human tumor specimens and primary spheroids from male and female patients that glial cell adhesion molecule (GlialCAM), which has normal roles in brain astrocytes and is mutated in the developmental brain disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC), is differentially expressed in subpopulations of GBM cells. High levels of GlialCAM promote cell-cell adhesion and a proliferative GBM cell state in the tumor core. In contrast, GBM cells with low levels of GlialCAM display diminished proliferation and enhanced invasion into the surrounding brain parenchyma. RNAi-mediated inhibition of GlialCAM expression leads to activation of proinvasive extracellular matrix adhesion and signaling pathways. Profiling GlialCAM-regulated genes combined with cross-referencing to single-cell transcriptomic datasets validates functional links among GlialCAM, Mlc1, and aquaporin-4 in the invasive cell state. Collectively, these results reveal an important adhesion and signaling axis comprised of GlialCAM and associated proteins including Mlc1 and aquaporin-4 that is critical for control of GBM cell proliferation and invasion status in the brain cancer microenvironment.SIGNIFICANCE STATEMENT Glioblastoma (GBM) contains heterogeneous populations of cells that coordinately drive proliferation and invasion. We have discovered that glial cell adhesion molecule (GlialCAM)/hepatocyte cell adhesion molecule (HepaCAM) is highly expressed in proliferative GBM cells within the tumor core. In contrast, GBM cells with low levels of GlialCAM robustly invade into surrounding brain tissue along blood vessels and white matter. Quantitative RNA sequencing identifies various GlialCAM-regulated genes with functions in cell-cell adhesion and signaling. These data reveal that GlialCAM and associated signaling partners, including Mlc1 and aquaporin-4, are key factors that determine proliferative and invasive cell states in GBM.

Collision tumor: Multinodular and vacuolating neuronal tumor with isocitrate dehydrogenase-mutant diffuse astrocytoma.

Herein, we report a case of a collision tumor involving a multinodular and vacuolating neuronal tumor (MVNT) and a diffuse astrocytoma. A collision tumor between these two entities has not previously been reported. The patient is a 35-year-old woman who presented with new-onset hearing loss and ringing in her right ear. Magnetic resonance imaging identified a non-enhancing mass involving the gray matter and subcortical white matter of the left middle frontal gyrus. Additionally, tiny clustered nodules were noted along the underlying subcortical ribbon and superficial subcortical white matter of the left superior frontal gyrus. The patient underwent a left frontal craniotomy and complete resection of the mass. Histologic examination of the resected specimen demonstrated a collision tumor consisting of a diffuse astrocytoma (isocitrate dehydrogenase [IDH] mutant, central nervous system [CNS] World Health Organization [WHO] grade 2) and an MVNT, with the latter demonstrating characteristic morphologic and immunohistochemical features.

A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.

The epigenetic dysfunction underlying malignant glioma pathogenesis.

Comprehensive molecular profiling has dramatically transformed the diagnostic neuropathology of brain tumors. Diffuse gliomas, the most common and deadly brain tumor variants, are now classified by highly recurrent biomarkers instead of histomorphological characteristics. Several of the key molecular alterations driving glioma classification involve epigenetic dysregulation at a fundamental level, implicating fields of biology not previously thought to play major roles glioma pathogenesis. This article will review the major epigenetic alterations underlying malignant gliomas, their likely mechanisms of action, and potential strategies for their therapeutic targeting.

Multi-omic molecular profiling reveals potentially targetable abnormalities shared across multiple histologies of brain metastasis.

The deadly complication of brain metastasis (BM) is largely confined to a relatively narrow cross-section of systemic malignancies, suggesting a fundamental role for biological mechanisms shared across commonly brain metastatic tumor types. To identify and characterize such mechanisms, we performed genomic, transcriptional, and proteomic profiling using whole-exome sequencing, mRNA-seq, and reverse-phase protein array analysis in a cohort of the lung, breast, and renal cell carcinomas consisting of BM and patient-matched primary or extracranial metastatic tissues. While no specific genomic alterations were associated with BM, correlations with impaired cellular immunity, upregulated oxidative phosphorylation (OXPHOS), and canonical oncogenic signaling pathways including phosphoinositide 3-kinase (PI3K) signaling, were apparent across multiple tumor histologies. Multiplexed immunofluorescence analysis confirmed significant T cell depletion in BM, indicative of a fundamentally altered immune microenvironment. Moreover, functional studies using in vitro and in vivo modeling demonstrated heightened oxidative metabolism in BM along with sensitivity to OXPHOS inhibition in murine BM models and brain metastatic derivatives relative to isogenic parentals. These findings demonstrate that pathophysiological rewiring of oncogenic signaling, cellular metabolism, and immune microenvironment broadly characterizes BM. Further clarification of this biology will likely reveal promising targets for therapeutic development against BM arising from a broad variety of systemic cancers.

The Evolving Classification of Diffuse Gliomas: World Health Organization Updates for 2021.

PURPOSE OF REVIEW: The upcoming 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System will feature numerous changes in classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. This article reviews these changes and the clinical and molecular findings underlying them. RECENT FINDINGS: Since the publication of the 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System, research has led to new insights into how molecular changes impact both the classification and grading of CNS tumors. The continued integration of molecular and histopathological features has led to changes in diagnostic criteria and grading for various tumors. In the new 2021 WHO CNS tumor classification scheme, diffuse gliomas will be classified as either adult-type diffuse gliomas, pediatric-type diffuse high-grade gliomas, or pediatric-type diffuse low-grade gliomas. The upcoming changes in the classification of adult-type and pediatric-type diffuse gliomas allow for more effective communication of both diagnostic and prognostic information, and-particularly in the case of pediatric-type diffuse gliomas-may suggest possible targeted strategies for therapeutic intervention.

Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

18F-Fluorocholine PET uptake correlates with pathologic evidence of recurrent tumor after stereotactic radiosurgery for brain metastases.

PURPOSE: Radiographic changes of brain metastases after stereotactic radiosurgery (SRS) can signify tumor recurrence and/or radiation necrosis (RN); however, standard imaging modalities cannot easily distinguish between these two entities. We investigated whether 18F-Fluorocholine uptake in surgical samples of the resected lesions correlates with pathologic evidence of recurrent tumor and PET imaging. METHODS: About 14 patients previously treated with SRS that developed radiographic changes were included. All patients underwent a preoperative 40-min dynamic PET/CT concurrent with 392 ± 11 MBq bolus injection of 18F-Fluorocholine. 18F-Fluorocholine pharmacokinetics were evaluated by standardized uptake value (SUV), graphical analysis (Patlak plot; KiP) and an irreversible two-compartment model (K1, k2, k3, and Ki). 12 out of 14 patients were administered an additional 72 ± 14 MBq injection of 18F-Fluorocholine 95 ± 26 minutes prior to surgical resection. About 113 resected samples from 12 patients were blindly reviewed by a neuropathologist to assess the viable tumor and necrotic content, microvascular proliferation, reactive gliosis, and mono- and polymorphonuclear inflammatory infiltrates. Correlation between these metrics 18F-Fluorocholine SUV was investigated with a linear mixed model. Comparison of survival distributions of two groups of patients (population median split of PET SUVmax) was performed with the log-rank test. RESULTS: Exactly 10 out of 12 patients for which surgical samples were acquired exhibited pathologic recurrence. Strong correlation was observed between SUVmax as measured from a surgically removed sample with highest uptake and by PET (Pearson's r = 0.66). Patients with 18F-Fluorocholine PET SUVmax > 6 experienced poor survival. Surgical samples with viable tumor had higher 18F-fluorocholine uptake (SUV) than those without tumor (4.5 ± 3.7 and 2.6 ± 3.0; p = 0.01). 18F-fluorocholine count data from surgical samples is driven not only by the percentage viable tumor but also by the degree of inflammation and reactive gliosis (p ≤ 0.02; multivariate regression). CONCLUSIONS: 18F-Fluorocholine accumulation is increased in viable tumor; however, inflammation and gliosis may also lead to elevated uptake. Higher 18F-Fluorocholine PET uptake portends worse prognosis. Kinetic analysis of dynamic 18F-Fluorocholine PET imaging supports the adequacy of the simpler static SUV metric.

Molecular markers and targeted therapy in pediatric low-grade glioma.

INTRODUCTION: Recently discovered molecular alterations in pediatric low-grade glioma have helped to refine the classification of these tumors and offered novel targets for therapy. Genetic aberrations may combine with histopathology to offer new insights into glioma classification, gliomagenesis and prognosis. Therapies targeting common genetic aberrations in the MAPK pathway offer a novel mechanism of tumor control that is currently under study. METHODS: We have reviewed common molecular alterations found in pediatric low-grade glioma as well as recent clinical trials of MEK and BRAF inhibitors. RESULTS: In this topic review, we examine the current understanding of molecular alterations in pediatric low-grade glioma, as well as their role in diagnosis, prognosis and therapy. We summarize current data on the efficacy of targeted therapies in pediatric low-grade gliomas, as well as the many unanswered questions that these new discoveries and therapies raise. CONCLUSIONS: The identification of driver alterations in pediatric low-grade glioma and the development of targeted therapies have opened new therapeutic avenues for patients with low-grade gliomas.

EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma.

PURPOSE: The highly vascular malignant brain tumor glioblastoma (GBM) appears to be an ideal target for anti-angiogenic therapy; however, clinical trials to date suggest the VEGF antibody bevacizumab affects only progression-free survival. Here we analyze a group of patients with GBM who received bevacizumab treatment at recurrence and are stratified according to tumor molecular and genomic profile (TCGA classification), with the goal of identifying molecular predictors of the response to bevacizumab. METHODS: We performed a retrospective review of patients with a diagnosis of glioblastoma who were treated with bevacizumab in the recurrent setting at our hospital, from 2006 to 2014. Treatment was discontinued by the treating neuro-oncologists, based on clinical and radiographic criteria. Pre- and post-treatment imaging and genomic subtype were available on 80 patients. We analyzed time on bevacizumab and time to progression. EGFR gene amplification was determined by FISH. RESULTS: Patients with classical tumors had a significantly shorter time on bevacizumab than mesenchymal, and proneural patients (2.7 vs. 5.1 vs. 6.4 and 6.0 months respectively, p = 0.011). Classical subtype and EGFR gene amplification were significantly associated with a shorter time to progression both in univariate (p < 0.001 and p = 0.007, respectively) and multivariate analysis (both p = 0.010). CONCLUSION: EGFR gene amplification and classical subtype by TCGA analysis are associated with significantly shorter time to progression for patients with recurrent GBM when treated with bevacizumab. These findings can have a significant impact on decision-making and should be further validated prospectively.

Effect of health disparities on overall survival of patients with glioblastoma.

BACKGROUND: Examine the potential effects of health disparities in survival of glioblastoma (GB) patients. METHODS: We conducted a retrospective chart review of newly diagnosed GB patients from 2000 to 2015 at a free standing dedicated cancer center (MD Anderson Cancer Center-MDACC) and a safety net county hospital (Ben Taub General Hospital-BT) located in Houston, Texas. We obtained demographics, insurance status, extent of resection, treatments, and other known prognostic variables (Karnofsky Score-KPS) to evaluate their role on overall GB survival (OS). RESULTS: We identified 1073 GB patients consisting of 177 from BT and 896 from MDACC. We found significant differences by ethnicity, insurance status, KPS at diagnosis, extent of resection, and percentage of patients receiving standard of care (SOC) between the two centers. OS was 1.64 years for MDACC patients and 1.24 years for BT patients (p < 0.0176). Only 81 (45.8%) BT patients received SOC compared to 577 (64%) of MDACC patients (p < 0.0001). However, there was no significant difference in OS for patients who received SOC, 1.84 years for MDACC patients and 1.99 years for BT patients (p < 0.4787). Of the 96 BT patients who did not receive SOC, 29 (30%) had KPS less than 70 at time of diagnosis and 77 (80%) lacked insurance. CONCLUSIONS: GB patients treated at a safety net county hospital had similar OS compared to a free standing comprehensive cancer center when receiving SOC. County hospital patients had poorer KPS at diagnosis and were often lacking health insurance affecting their ability to receive SOC.

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors.

BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Metachronous Medulloblastoma in a Child With Successfully Treated Neuroblastoma: Case Report and Novel Findings of DNA Sequencing.

Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.

Multiplatform profiling of meningioma provides molecular insight and prioritization of drug targets for rational clinical trial design.

INTRODUCTION: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents. METHODS: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status. RESULTS: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%). CONCLUSION: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.

Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas.

Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-α (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRA(Δ8, 9), an intragenic deletion rearrangement. The PDGFRA(Δ8, 9) mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated.