bluuebunny/crossref_metadata_2025 huggingface dataset:
EPID-25. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Bennett Julie , Nobre Liana , Sheth Javal , Ryall Scott , Fang Karen , Johnson Monique , Negm Logine , Chung Jiil , Komosa Martin , Nunes Nuno , Lim-Fat Mary Jane , Perry James , Sahgal Arjun , Detsky Jay , Bouffet Eric , Hazrati Lili-Naz , Dirks Peter , Ertl-Wagner Birgit , Kongkham Paul , Zadeh Gelareh , Mason Warren , Cusimano Michael , Das Sunit , Gao Andrew , Tsang Derek , Nguyen Lananh , Laperriere Normand , Keith Julia , Munoz David , Tabori Uri , Hawkins Cynthia
Published: November 2022

OBJECTIVE

Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach. Molecular alterations have not been comprehensively described to date.

METHODS

We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years.

RESULTS

A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH p.R132H was found in 49% of tumours, while non-canonical IDH mutations were found in 7%. Paediatric-type mutations were found in 33% of AYA tumours with IDH-WT GBM accounting for the remaining 11%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (7%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients > 20 years suggesting malignant transformation possibly due to higher rate of secondary hits. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years.

CONCLUSIONS

Gliomas in AYA often have non-canonical alterations that may evade standard molecular analysis. They are enriched for paediatric-type alterations with distinct molecularly-based outcomes. These tumours may respond to targeted inhibitors and would benefit from comprehensive diagnostic and therapeutic approaches.
EPCO-01. EPIGENETIC REPROGRAMMING SHAPES THE MOLECULAR AND CELLULAR LANDSCAPE OF SCHWANNOMA
Authors: John Liu S , Casey-Clyde Tim , Swinderman Jason , Cho Nam Woo , Vasudevan Harish , Foster Kyla , Pekmezci Melike , Chen William , Villanueva-Meyer Javier , Hiam-Galvez Kamir J , Swaney Danielle , Choudhury Abrar , Breshears Jonathan , Stevenson Erica , Chen Kuei-Ho , Lien Brian , Wu David , Lang Ursula , Magill Stephen , Lim Daniel , McDermott Michael , Berger Mitchel S , Perry Arie , Krogan Nevan J , Spitzer Matthew , Gilbert Luke , Theodospoulos Philip , Raleigh David
Published: November 2022

DNA methylation profiling provides robust classification of nervous system tumors, but mechanisms driving epigenetic identity of individual tumor types are incompletely understood. Integrating DNA methylation profiling (n=76), RNA sequencing (n=24), single-cell RNA-sequencing (n=9), and mass cytometry (n=9), we discovered vestibular schwannomas are comprised of two epigenetic groups distinguished by neural crest development pathways or repair and regeneration pathways driving immune infiltration. Analyses of preoperative magnetic resonance imaging studies (n=66) or paired primary and recurrent schwannomas (n=13) suggested radiotherapy was sufficient but not necessary for epigenetic reprogramming of neural crest enriched schwannomas into immune enriched schwannomas. In support of this hypothesis, DNA methylation profiling, RNA sequencing, single-cell RNA sequencing, proteomic mass spectrometry, and lymphocyte migration assays demonstrated radiotherapy epigenetically reprogramed viable schwannoma cells to secrete immunomodulatory signals and recruit lymphocytes in vitro. Genome-wide CRISPRi screens identified histone acetyltransferases or DNA methyltransferases driving schwannoma radiotherapy responses, including the epigenetic regulators KDM5C or KDM1A. CRISPRi and lymphocyte migration assays ± radiotherapy confirmed KDM5C drives schwannoma immune infiltration whereas KDM1A inhibits schwannoma immune infiltration. To define genomic mechanisms underlying epigenetic group identity, we performed pooled CRISPRi screening coupled with single-cell RNA sequencing (Perturb-seq) of 44 schwannoma markers. In parallel, we developed single nuclei profiling of chromatin accessibility through paired ATAC sequencing and RNA sequencing coupled with pooled CRISPRi screening (snARC-seq) of 54 epigenetic regulators identified by our genome-wide CRISPRi screen. Functional genomic approaches revealed the tyrosine phosphatase PTPRG as a regulator of survival, and KDM5C and KDM1A as regulators of inflammation. In summary, we report two epigenetic groups of schwannomas and mechanisms underlying epigenetic group identity using a new functional genomic technique allowing for simultaneous interrogation of single-cell epigenetic and gene expression changes in the context of genetic and therapeutic perturbations. These data elucidate a novel epigenetic mechanism of action of radiotherapy.
EPCO-02. GENOME-WIDE DNA METHYLATION PROFILING AND GENETIC CHARACTERIZATION OF LONG-TERM SURVIVAL IDH WILD-TYPE GLIOBLASTOMA PATIENTS
Authors: Miele Evelina , Lazzarini Elisabetta , Ciolfi Andrea , Pedace Lucia , Nardini Claudia , Patrizi Sara , Mastronuzzi Angela , Tartaglia Marco , Anghileri Elena , Calatozzolo Chiara , Lamperti Elena Antonia , Patanè Monica , Locatelli Franco , Indraccolo Stefano , Pollo Bianca
Published: November 2022

Glioblastoma multiforme (GBM) has a dismal outcome of approximately 12 months. Less than 5% of patients (long-term survivors-LTS) survives more than 5-years, including IDH-mutant gliomas. Nevertheless, the molecular fingerprint of LTS remains largely uncharted. DNA methylation (DNAm) is an epigenetic modification, altered in cancer and used to classify brain tumors. In this multicentric study sponsored by Alleanza Contro il Cancro (ACC) network, we aimed to molecularly characterize LTS vs standard survival GBM (CTR) by DNAm/Copy Number Variation (CNV) and mutation profiling. We analyzed 51 IDHwt GBM samples (27LTS/24CTR) by Illumina EPIC beadChip and AmpliSeq Comprehensive Cancer Panel. We ran methylation data through the brain tumor classifiers v11b4 and v12.5, performed multidimensional scaling analysis and investigated differentially methylated regions (DMR) correlating them with survival. According to v11b4, cases were classified as: 43 GBM IDHwt (22LTS/21CTR), 27 with a calibrated score >0.84 (16LTS); Plexus Tumor with low scores (2LTS/3CTR); 3 LTS samples did not match. A diagnostic refinement was observed by the v12.5, with 48 cases classifying as GBM IDHwt (25LTS/23CTR) and 35 (19LTS) with optimal score. The LTS group was more heterogeneous, with 4 cases matching in the pedHGG subtypes, including 2 cases in young adults, one with high tumor mutational burden and MSH6 mutation. No specific DNAm genomic profile was observed for LTS patients but we identified 18 significant DMRs, 4 associated with survival probability. At CNV analysis, most cases showed classical alterations (Chr7 gain with or w/o EGFR amplification, 9p21 loss, Chr10 loss) while pedHGG were associated with PDGFRA amplification, 1q gain, 13q loss. NGS identified at least 1 pathogenic variant in 40 cases (22CTR/18LTS) and showed a higher prevalence of mutation negative cases among LTS. No significant difference between the 2 groups was observed in terms of prevalence of mutated genes or number of VUS per sample.
EPCO-03. PATHWAY-BASED STRATIFICATION OF GLIOBLASTOMA BY MULTI-OMICS INFORMS SUBTYPE-SPECIFIC MASTER KINASES-PHOSPHOSITE SUBSTRATES
Authors: Migliozzi Simona , Oh Young Taek , Hasanain Mohammad , Garofano Luciano , D'Angelo Fulvio , Picca Alberto , Bielle Franck , Sarkaria Jann , Ceccarelli Michele , Sanson Marc , Lasorella Anna , Iavarone Antonio
Published: November 2022

Tumor heterogeneity and broad therapeutic resistance are major challenges when treating patients with glioblastoma (GBM). Moreover, different from other cancer types, the absence of clinically useful classifiers for glioblastoma has hampered the translation of genomic and proteomic information to improve diagnosis and design precision therapeutics for patients. We analyzed a large dataset of human GBM to determine the multi-omics features characterizing the four GBM subtypes that we have recently identified through single-cell RNA sequencing and validated in bulk tumor analysis. Each subtype exhibits activation of unique functional traits that confer distinct therapeutic vulnerabilities. The examination of proteomics, phosphoproteomics, metabolomics, lipidomics and acetylomics data revealed that each GBM subtype has a coherent molecular structure driving the dominant function traceable in each analytical platform. Functional classes are not a specific attribute of GBM as we identified the same subtypes in breast and lung cancer. To test the translational impact of proteomic data in GBM, we developed an unbiased protein kinase signaling network approach for the selection of master kinases (MKs) aberrantly activated in each GBM subtype. We identified therapeutically actionable MKs and novel phosphorylation substrates that we experimentally validated. To provide rapid translation of the functional classifier for precision medicine in GBM, we developed a probabilistic classification tool which determines the probability that a patient’s GBM belongs to one of the four subtypes, exhibiting optimal performance when using RNA extracted from either frozen and paraffin-embedded tissues. The algorithm is publicly accessible and can be used to evaluate the association of therapeutic response with GBM subtypes and as tool for selection criteria in prospective clinical trials.
EPCO-05. DIFFERENTIAL MOLECULAR PROFILING OF IDH WILD TYPE GLIOBLASTOMA SURVIVORS REVEALS THE ASSOCIATION OF NEOANTIGEN QUALITY WITH EXCEPTIONAL LONG SURVIVAL
Authors: D'Angelo Fulvio , Garofano Luciano , Aoki Kosuke , Ceccarelli Michele , Lasorella Anna , Sanson Marc , Iavarone Antonio
Published: November 2022

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor. Despite intensive multimodal treatment, the prognosis of GBM patients is poor with the median overall survival under 15 months. Defining the genetic profiles of rare long-term GBM survivors may provide insights into the molecular basis of GBM progression. IDH mutations have been identified as a favorable prognostic factors, and define a clinically and molecularly distinct group of GBM. Additional molecular mechanisms underlying the prolonged survival in IDHwt GBM patients remained unclear. Therefore, we explored the molecular profiles of 71 IDHwt GBM homogeneously treated patients exhibiting disproportionate survival. The cohort included 36 short-term survivors that deceased within 1 year after diagnosis (median survival of 7 months) and 35 long-term survivors exhibiting an exceptional survival above 4 years (median survival of 88 months). The differential genetic landscape of short- and long-term IDHwt GBM survivors outlined similar mutation load and few differences in the frequency of recurrent alterations, including chromosomes 19 and 20 duplication significantly overrepresented in long-term survivors. To assess the potential impact of T lymphocyte neoantigen-mediated activation towards extended GBM survival, we inferred the restricted HLA binding affinity of the somatic mutations and applied the immune fitness model to accurately predict high-quality neoantigens. Although the general neoantigen burden remained unvaried between short- and long-term survivors, we found that the immune quality of the predicted neoantigens is significantly higher in the patients with exceptional long survival. Moreover, the immune deconvolution of the tumor microenvironment from the gene expression data indicated the presence of CD8+ T lymphocytes and pro-inflammatory macrophages in samples harboring high-quality neoantigens from long-term survivors. This study identified the neoantigen quality as a main distinctive feature of exceptionally long-term survivors supporting the key role of cellular-mediated immune response to restrict tumor progression in IDHwt GBM.
EPCO-06. THE IMPACT OF MISMATCH REPAIR DEFICIENCY (MMRD) ON SURVIVAL OF TEMOZOLOMIDE (TMZ)-TREATED PATIENTS WITH MGMT METHYLATED (M-MGMT) GLIOBLASTOMA (GBM): A CELLWORKS COMPUTATIONAL BIOSIMULATION PILOT STUDY
Authors: Castro Michael , Iwamoto Fabio , Ahluwalia Manmeet , Usmani Shahabuddin , Kumar Ansu , Kapoor Shweta , Suseela Rakhi Purushothaman , Kulkarni Shruthi , Mohanty Jharana , Shyamasundar Vijayashree , Ghosh Adity , Prasad Nagendra , Patil Mamatha , Choudhury Sayantani Roy , Chauhan Jyoti , Sauban Mohammed , Joseph Vishwas , Kumari Pallavi , Mitra Upasana , Pampana Anusha , Azam Humera , G Poornachandra , Prakash Annapoorna , Basu Sayani
Published: November 2022

BACKGROUND

TMZ-induced G:T mismatches trigger MMR to perform futile repair of O6-methylguanine leading to apoptosis. Without MMR, the G:T mutation is genomically incorporated to produce DNA mutation signature #11. Hypermutation ensues and may compromise survival without the redemptive benefit of immunotherapy. MMR genes are infrequently mutated or deleted. More commonly, MMRD results from epigenetic silencing, transcription failure, or micro-RNA compromising translation.

METHODS

Comprehensive genomic profiling and Cellworks biosimulation was utilized to diagnose MMRD and correlated with survival in 38 TCGA patients with newly diagnosed, IDH wildtype, m-MGMT GBM treated with adjuvant TMZ. The signaling pathway consequences for MutSα and MutLα were assessed. Kaplan-Meier curves were constructed for PFS and OS.

RESULTS

Patients were characterized: MMR proficient (Grp 1) and deficient (Grp 2). Half (19/38) had compromise of 1-10 pathways impacting MMR: 3 had deletions of MLH1 or PMS2. Others included deletions of EP300, CREBBP, KMT2A-D, ARID1A, HUS, or EXO1 and amplifications of KDM4A/C or MIR21/155. Grp 1 had significantly higher MMR biosimulation scores than Grp 2. (p=0.00082). The median PFS was 10.51 and 3.58 months (p=0.0072) and median OS was 16.96 and 9.40 (p=0.0059) months in Group 1&2, respectively.

CONCLUSIONS

Up to half of GBM patients have MMRD caused by pathway dysregulation. Biosimulation of MMRD predicts early progression on TMZ, echoing the long-held observation that TMZ does not trigger apoptosis in MMRD cancers. The study also reports inferior OS for MMRD compared to the historical experience of unmethylated-MGMT patients, suggesting that TMZ-induced hypermutation may compromise survival. As lomustine does not rely on intact MMR, 2nd-line lomustine may have blunted the impact of MMR on OS. Alternatively, upfront lomustine might have produced superior disease control in MMRD patients. Computational biosimulation offers the opportunity to diagnose patients who should not receive TMZ despite m-MGMT and who could benefit from alternative adjuvant strategies.
EPCO-09. TRANSCRIPTOMIC LANDSCAPE OF LOWER GRADE GLIOMA BASED ON AGE-RELATED NON-SILENT SOMATIC MUTATIONS
Authors: Sung Kyoung Su , Lim Jaejoon
Published: November 2022

Glioma accounts for 80% of all malignant brain tumours and is the most common adult primary brain tumour. Age is an important factor affecting the development of cancer, as somatic mutations accumulate with age. Here, we aimed to analyse the significance of age-dependent non-silent somatic mutations in glioma prognosis. Histological tumour grade depends on age at diagnosis in patients with IDH1, TP53, ATRX, and EGFR mutations. Age of patients with wild-type IDH1 and EGFR increased with increase in tumour grade, while the age of patients with IDH1 or EGFR mutation remained constant. However, the age of patients with EGFR mutation was higher than that of patients with IDH1 mutation. The hierarchical clustering of patients was dominantly separated by IDH1 and EGFR mutations. Furthermore, patients with IDH1 mutation were dominantly separated by TP53 and ATRX double mutation and its double wild-type counterpart. The age of patients with ATRX and TP53 mutation was lower than that of patients with wild-type ATRX and TP53. Patients with the double mutation showed poorer prognosis than those with the double wild type genotype. Unlike IDH1 mutant, IDH1 wild-type showed upregulation of expression of epithelial mesenchymal transition associated genes.
EPCO-12. SEX-SPECIFIC PATTERNS CONNECTING LOCOREGIONAL MRI FEATURES AND IMMUNOHISTOCHEMISTRY OF IMAGE-LOCALIZED BIOPSIES OF GLIOBLASTOMA
Authors: Langworthy Jazlynn , Jackson Pamela , Hawkins-Daarud Andrea , Ranjbar Sara , Singleton Kyle , Boyett Deborah , Argenziano Michael , Grinband Jack , Canoll Peter , Swanson Kristin
Published: November 2022

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 14 months. GBMs are challenging to treat due to their heterogeneous nature. It has also been seen that these tumors have sex differences in their cellular subtypes as well as imaging. Radiomics has the potential to provide a non-invasive, spatial understanding of genetic and epigenetic diversity in these complex tumors and to aid in treatment planning. We have an ongoing study to obtain image-localized biopsies from GBM patients, allowing us to complete radiomic analysis and make connections between immunohistochemistry (IHC) and magnetic resonance imaging (MRI) features. We sought to determine if the patterns on imaging were correlated with underlying tumor biology. We focused on immunohistochemistry (IHC) markers of key features of tumor biology including SOX2 for stem-like tumor cells, CD68 for immune response and Ki67 for proliferation kinetics. Our study included 38 patients with a total of 99 biopsies (bxs): 27 males with 77 bxs and 11 females with 22 bxs. Biopsies were sectioned and stained for the SOX2, CD68, and KI67 markers. We computed 18 first-order radiomic features at each biopsy location for patients’ multimodal MRIs: T1W, T1Gd, T2W, FLAIR, apparent diffusion coefficient, diffusion weighted imaging (DWI) and susceptibility weighted imaging. We then performed correlation analysis between each radiomic feature and marker abundance for each IHC stain. Overall, we found sex-distinct patterns connecting imaging with these IHC markers. For example, amongst female patients, DWI held more prominent correlations with SOX2 than in males. Whereas there were more correlations between CD68 IHC abundance and T1Gd imaging features in males compared to females. Taken together, the overall patterns connecting locoregional imaging features to these IHC markers showed sex-distinct patterns suggesting the potential for sex to be an important biological variable when interpreting the biology underlying imaging changes.
EPCO-16. ESTIMATING THE DIFFERENTIATION POTENTIAL AND PLASTICITY OF GLIOBLASTOMA CELLS USING STATISTICAL MECHANICS
Authors: Lång Adam , Larsson Ida , Jörnsten Rebecka , Nelander Sven
Published: November 2022

Glioblastoma (GBM) is the most common form of adult brain tumors and patients diagnosed with GBM face a very dismal prognosis with a median survival rate of 15 months. The challenges in treating GBM are many, there is a complex cellular and molecular heterogeneity, both between patients and within individual tumors. In a single tumor, individual cancer cells adopt a variety of stem-like, progenitor-like, and more differentiated phenotypes (a.k.a. cell states). Recent advances in single-cell technology have made it possible to detect this diversity of cellular states, but yet we lack a good explanation for how the states arise and if transitions between states can be exploited to therapeutic ends. We here propose a new computational strategy to measure the differentiation potential of GBM cells, based on the Ising models from statistical mechanics. Originally used to model coupled magnets on a lattice, the Ising models can be generalized to represent the probability of a particular configuration of any system of n variables. We show that the models can be fitted to high-dimensional single cell data in a matter of seconds by solving a convex optimization problem, and that the models help explain cell differentiation in terms of minimization of an energy function of the system. In our on-going work we have fitted the model to single cell data from our previous work on state transitions in GBM (Larsson, Dalmo et al, Molecular Systems Biology 2021) and shown that the predicted differentiation potential of cell states is consistent with the cell state hierarchies derived from lineage tracing experiments. Moving forward, we are now exploring how the Ising models can be used to model state transitions in GBM and to predict the effect of targeted therapy on the cell’s differentiation potential.
EPCO-21. THE SPATIAL ORGANIZATION OF H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Liu Ilon , Li Jiang , Samuelsson Erik , Salas Sergio Marco , Beck Alexander , Hack Olivia , Jeong Daeun , Shaw McKenzie , Englinger Bernhard , Labelle Jenna , Mire Hafsa , Madlener Sibylle , Mayr Lisa , Quezada Michael , Trissal Maria , Panditharatna Eshini , Ernst Kati , Gatesman Taylor , Halbert Matthew , Palova Hana , Pokorna Petra , Sterba Jaroslav , Slaby Ondrej , Geyeregger Rene , Diaz Aaron , Resnick Adam C , Suva Mario , Jones David , Agnihotri Sameer , Ostlin Jessica , Koschmann Carl , Haberler Christine , Czech Thomas , Slavc Irene , Cotter Jennifer , Ligon Keith , Alexandrescu Sanda , Yung W K Alfred , Arrillaga-Romany Isabel , Gojo Johannes , Monje Michelle , Nilsson Mats , Filbin Mariella
Published: November 2022

Histone 3 lysine27-to-methionine mutant diffuse midline gliomas (H3-K27M DMGs) are among the most lethal brain tumors. Their putative cellular hierarchy has been shown to be driven by self-renewing stem-like cells arrested in an oligodendrocyte precursor-like (OPC-like) state, of which few cells are able to differentiate towards more mature astrocyte (AC)-like and oligodendrocyte (OC)-like cells. However, the spatial organization underlying this tumor cell architecture and its microenvironmental interactions in intact H3-K27M DMG tissues remain unknown. Here, we profiled the single cell transcriptomes of 45 patient H3-K27M DMGs and derived cell population-specific marker gene combinations to characterize the single cell spatial organization of 16 tumors using targeted in situ sequencing. We thereby resolved different malignant and non-malignant cell populations including cycling, OPC-like, AC-like, OC-like, mesenchymal tumor cells, and non-malignant oligodendrocytes, astrocytes, neurons, myeloid cells, T cells, and vascular cells directly in situ. Global neighborhood analyses indicate a higher tendency of cycling OPC-like cells, vascular cells, and neurons to localize within a more restricted homogeneous compartment, whereas AC-like cells, non-malignant astrocytes and myeloid cells tend to intermingle with different cell populations in a more diffuse manner. Among malignant cells, we observed cycling OPC-like and OC-like cells to co-localize within a niche-like structure that is surrounded by more differentiated AC-like cells. We further validated this stem-like niche at the protein level using multiplexed immunofluorescence via the CODEX system. Finally, we characterized relationships between malignant and non-malignant cells, consistently identifying preferred neighborhoods of mesenchymal tumor cells with vascular and myeloid cells. Together, this study resolves the spatial architecture of H3-K27M DMG malignant and non-malignant cells at single cell resolution and identifies a local niche of the oligodendroglial lineage containing the OPC-like cancer stem-like cells, thus providing novel insights into the cancer stem-like compartment in H3-K27M DMGs and suggesting potential avenues for its perturbation.
EPCO-23. DYSFUNCTION OF LARGE H3K9ME3 DOMAINS IN ATRX DEFICIENT GLIOMAS INDUCES GENETIC REARRANGEMENTS AND LATENT DEVELOPMENTAL SIGNALING NETWORKS THROUGH SUPER-ENHANCER LANDSCAPES
Authors: Malgulwar Prit Benny , Danussi Carla , Singh Anand , Saw Ajay Kumar , Rai Kunal , Huse Jason
Published: November 2022

Somatic alterations in ATRX (Alpha Thalassemia/Mental Retardation Syndrome X-linked), a member of SWI/SNF family chromatin regulator has been found to be frequently mutated in diffuse gliomas and defines molecular subtypes with aggressive behavior. Mechanistically, ATRX regulates incorporation of histone H3.3 into chromatin sites across the genome, maintains alternative lengthening of telomeres and establishes genomic distribution of polycomb responsive genes. To understand in depth role of ATRX in gliomas, we performed ChIP-seq and/or Cut-and-tag for histone marks that define active transcription, enhancers, repressors, gene bodies and CTCF on Atrx intact and deficient mNPCs (mouse Neural Progenitor Cells). Our integrated analysis reports depletion of H3K9me3 loci’s that coincidently enriched with Atrx binding sites and Lamina-Associated Domains with genes enriched for cell cycle, motility and chromosome organization. This chromatin perturbations at heterochromatin domains was further confirmed in our Hi-C analysis with switching of A-B and B-A compartments, reorganization of TADs with occasional CTCF marks and gain of novel interacting loops that showed gene expression leakage required for gliomagenesis using Capture Hi-C. Notably, we observed aberrant levels of endogenous retroviral elements (ERVs) family members, including upregulation of Line-1 elements in mNPCs and patient derived glioma stem cells (GSCs) and our analysis shows increased copy number variations in ATRX deficient gliomas as a consequence of Line-1 activation in these subsets of tumors. Finally, our integrated omics- analysis demonstrates enrichment of super-enhancers in Atrx deficient background with several putative druggable candidates for clinical benefits. As an example, we show presence of H3K27ac super-enhancer over HOXA locus and targeting pan-HOXA genes using small inhibitor peptides diminished proliferation and migration of mNPCs and GSCs with increased in cell apoptosis with alterations in downstream developmental signaling pathways. To summarize,our data establishes tangible links between Atrx deficiency and multiscale dysregulated cellular phenotype in gliomas with identifying novel targets for therapy.
EPCO-34. INTEGRATIVE DNA METHYLATION ANALYSIS OF PEDIATRIC BRAIN TUMORS REVEALS TUMOR TYPE-SPECIFIC DEVELOPMENTAL TRAJECTORIES AND EPIGENETIC SIGNATURES OF MALIGNANCY
Authors: Pekkarinen Meeri , Nordfors Kristiina , Uusi-Mäkelä Joonas , Kytölä Ville , Rauhala Minna , Urhonen Henna , Häyrynen Sergei , Afyounian Ebrahim , Yli-Harja Olli , Zhang Wei , Helen Pauli , Lohi Olli , Haapasalo Hannu , Haapasalo Joonas , Nykter Matti , Kesseli Juha , Granberg Kirsi
Published: November 2022

Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. Recently DNA methylation has proven to be powerful for brain tumor characterization and diagnostic classification. To evaluate tumor type specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas (MBs), and choroid plexus tumors with each other by integrating DNA methylation (507 samples), gene expression (120 samples), and transcription factor (TF) -binding data. Different tumor entities were used to find unique changes affecting each of the entities and further to identify functions driven by these changes. Our results provide insight on how the aberrant DNA methylation induces oncogenesis of AT/RTs. These tumors are known for their aggressiveness and exceptionally low mutation rates. Our results suggest that in AT/RT, elevated DNA methylation masks the binding sites of TFs such as NEUROD1, ASCL1 and MYCN driving neural development. DNA methylation in AT/RTs is also associated with reduced gene expression for specific neural regulators such as NEUROG1 and NEUROD2. For MBs, DNA methylation patterns predict a more advanced differentiation state. In MB, we found masked TF binding sites for TFs such as REST and ZEB1 that normally inhibit neural differentiation. We then wanted to further characterize DNA methylation and compared these tumors to pluripotent stem cells (PSCs) and normal fetal brain samples. As a result, we were able to find two different regulatory programs in AT/RTs: One in which DNA methylation is similar to PSCs and which harbors mostly neural TF binding sites. Second program has AT/RT-specific DNA methylation, and these sites are uniquely associated with polycomb repressive complex 2 members. However, this second program also covers neural TF binding sites and is likely to have relevance in oncogenic regulation.
EPCO-36. INVESTIGATING THE BAIAP2-CDC42 INTERACTION IN MEDULLOBLASTOMA
Authors: Ruiz Luz , Jangde Nitish , Ayad Nagi
Published: November 2022

Medulloblastoma is the most common malignant brain tumor found in children. The standard of care is surgical removal, radiation, and chemotherapy. Despite advancements in treatment, there is still no significant improvement of survival rates using chemotherapy compared to no treatment. This indicates novel, more effective treatment options are necessary. In addition, there is a worst mortality rate when medulloblastoma is metastasized outside the central nervous system. Recent studies have identified that medulloblastoma tumors can disseminate via the bloodstream and cerebral spinal fluid. However, not much is known about the properties of metastasis and invasion in medulloblastoma. We set out to identify potential key regulators for the pathophysiology of medulloblastoma. I mined and analyzed Medulloblastoma patient tumor data along with data obtained from a 10X Genomics Chromium single-cell RNA sequencing experiment performed in the laboratory from a Tg (Neurod-Smoothened*A1) mouse to investigate cellular heterogeneity and identify potential regulators in the metastasis and invasion of medulloblastoma. We identified BAIAP2 and CDC42 to be differentially expressed in our data. Previous studies show that these genes are implicated in oncogenic properties, such as motility, filopodia, and invasion. We hypothesize that distinct cell populations within medulloblastoma should show different expressions of BAIAP2 and CDC42 and that there will be different expressions when compared to non-tumor brain cells. We determined that BAIAP2 and CDC42 have higher expression in medulloblastoma tumors compared to the control. Interestingly, BAIAP2 is enriched in the cell population for microtubule depolymerization. Moreover, we show the role BAIAP2 and CDC42 have in the invasion and metastasis of medulloblastoma. This study is important because BAIAP2 and CDC42 have yet to be characterized in medulloblastoma. We suggest that BAIAP2 and CDC42 have a role in the metastasis and invasion of medulloblastoma indicating it could be a possible target for future studies.
EPCO-38. TYPE B ULTRA LONG-RANGE INTERACTIONS IN PFAS (TULIPS) ARE RECURRENT EPIGENOMIC FEATURES OF PFA EPENDYMOMA
Authors: Johnston Michael , Lee John J Y , Hu Bo , Nikolic Ana , Baguette Audrey , Paik Seungil , Chen Haifen , Kumar Sachin , Chen Carol , Jessa Selin , Balin Polina , Fong Vernon , Zwaig Melissa , MichealRaj Kulandaimanuvel , Chen Xun , Zhang Yanlin , Varadharajan Srinidhi , Billon Pierre , Juretic Nikoleta , Daniels Craig , Giannini Caterina , Thompson Eric , Hauser Peter , Kim Seung-Ki , Wang Kyu-Chang , Lee Ji Yeoun , Grajkowska Wieslawa , Agnihotri Sameer , Mack Stephen C , Ellezam Benjamin , Weil Alex , Bourque Guillaume , Chan Jennifer , Lupien Mathieu , Ragoussis Jiannis , Kleinman Claudia , Majewski Jacek , Jabado Nada , Taylor Michael , Blanchette Mathieu , Gallo Marco
Published: November 2022

Posterior Fossa Group A (PFA) ependymomas are pediatric brain tumors with extremely poor survival outcomes. As protein-coding mutations in PFA are exceedingly rare, the underlying etiology of these tumors remains elusive. Elevated CpG island methylation and depletion of H3K27me3 have been described in PFA, leading to the hypothesis that PFA may be driven by a dysregulated epigenetic state. In this study, we sought to determine how three-dimensional (3D) genome features (such as DNA loops, domains, and compartments) differ between pediatric brain tumors. We performed Hi-C sequencing on a collection of 64 patient specimens and patient-derived primary cultures that collectively span multiple subgroups of ependymoma, medulloblastoma, high-grade glioma, and non-neoplastic brain. For certain samples, we further performed RNA-seq, histone modification ChIP-seq, or whole-genome bisulfite sequencing to allow multiomic data integration. Overall, the 3D genome organization of PFA samples appeared distinct from other tumor types. We identified and defined TULIPs: a subset of type B compartments, separated by genomic distances greater than 10 Mbp, that exhibit a striking fivefold increase in reciprocal interaction strength. These TULIPs recurred at the same genomic positions across the vast majority of PFA samples with minimal representation among other tumor or non-tumor samples. TULIPs displayed enrichment for heterochromatic features such as H3K9me3 and late replication timing and were depleted of euchromatic features such as H3K27ac and protein-coding genes. By using immuno-fluorescence for H3K9me3 and oligo-FISH to label TULIP regions, we demonstrated that TULIP regions are more compact in PFA than other tumors. Finally, by applying inhibitors of H3K9 lysine methylation to PFA cultures we showed that TULIPs become more diffuse and cell viability is reduced. Altogether, this work defines TULIPs as highly recurrent epigenetic features of PFA tumors.
EPCO-41. DNA METHYLATION PROFILING OF MENINGIOMAS FROM 17 PATIENTS, A CASE SERIES
Authors: Shen Erica , Leclair Nathan , Herlth Kristi , Soucy Melissa , Renzette Nick , Zhuo Xinming , Kelly Kevin , Omerza Gregory , Wolansky Leo , Becker Kevin , Li Lei , Wu Qian , Bulsara Ketan
Published: November 2022

BACKGROUND

Meningiomas are the most common intracranial tumors. According to the World Health Organization’s (WHO) classification guidelines, they can be classified into 15 subtypes with three grades of malignancy based on histology alone. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success. Method: In our case series, we report DNA methylation profiling on meningiomas from 17 patients. Formalin fixed paraffin embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were then processed through the v12b6 version of the CNS tumor classifier developed by the Molecular Neuropathology group at the University of Heidelberg. Classifier output consisted of assigned methylation classifications along with confidence scores, with scores ≥0.84 classified as “high confidence.” Result: Among our meningioma samples from 17 patients (18 samples total), 14 samples are classified as “benign,” one sample is classified as “intermediate,” and the remaining three samples from two patients are classified as “malignant.” In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (size, location), surgical approaches, and mutational analysis. Genomic analysis has revealed variants in NF2, SLX4, ARID1A, KDM4C, ERCC2, EP300, ERBB2, KMT2D, LRP1B, FANCE, CRKL, and SPEN in multiple patients. The three meningioma samples from the two patients that are classified as “malignant” all have a high MIB1 indexes consistent with WHO Grade II meningiomas. Both patients had tumor recurrence reflecting the aggressiveness of the tumor in their disease course.

CONCLUSION

In accordance with prior reports, our case series provides support that tumor DNA methylation profiling can provide useful classification information and can be correlated to both tumor pathology and patient clinical presentation.
EPCO-43. CHROMATIN REMODELERS LOST IN TRANSLATION
Authors: Van Rechem Capucine
Published: November 2022

The chromatin remodeler complexes mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) are altered in more than 40% of cancers and are involved in therapeutic resistance. In children,SMARCB1 is mutated in 95% of rhabdoid tumors, and the remaining 5% present mutations in SMARCA4. These tumors are typically identified in children younger than three years old and have a very poor prognosis with a survival under one year following diagnosis. SMARCB1 expression is also lost in more than 90% of epithelial sarcomas, a rare and aggressive tumor affecting young adults, and in 50% of pediatric chordomas. Additional mSWI/SNF subunits are also highly mutated in childhood cancers such as ARID1A and ARID1B in neuroblastomas, the most common solid tumor in children, and the ARID subunits and SMARCA4 in medulloblastomas, the most common brain cancer in children. To date, mSWI/SNF roles in normal and cancer cells are still largely undetermined and focus on nuclear functions. However, our assessment of genetic dependencies and drug sensitivity screens revealed that cancer cells mutated for mSWI/SNF are genetically dependent and exclusively sensitive to translation factors and translation pathway inhibitors. We demonstrate that mSWI/SNF complexes are extensively localized in the cytoplasm and that they interact with the translation initiation machinery. Furthermore, short-term inhibition, depletion and cancer mutations of specific subunits alter protein synthesis and increase sensitivity to translation inhibitors. Most mutations in these complexes being considered loss of function, these results suggest a potential therapeutic opportunity for diseases presenting mutations in these complexes. In conclusion, our work demonstrates the chromatin remodelers mSWI/SNF have direct roles in translation that will not only be relevant for the molecular understanding of cancer but also lead to new therapeutic opportunities.
DISP-08. DISPARITY OF RADIATION TREATMENT AND CLINICAL OUTCOME AMONG ADULT MEDULLOBLASTOMA PATIENTS
Authors: Yang Kailin , Dinh Mina , Nam Kireem , Madishetty Sanjana , Kilic Sarah , Scott Jacob , Chao Samuel , Murphy Erin , Suh John
Published: November 2022

OBJECTIVES

Medulloblastoma is the most common malignant pediatric brain neoplasm, but its pattern of care among adult patients has not been standardized. Disparity in socioeconomic factors influence treatment decision and prognosis in many cancers. This study aims to analyze the impact of insurance and socioeconomic status on the clinical outcome of adult patients with medulloblastoma in the United States.

METHODS

Adult patients (age 18 or older) with medulloblastoma in the brain diagnosed from 2004 to 2016 were identified from the National Cancer Database (NCDB). OS was evaluated with the Kaplan-Meier and Cox proportional hazards methods. Logistic regression was performed to assess the effect on dichotomized dependent variable.

RESULTS

A total of 1,282 adult patients with medulloblastoma were identified. The mean age was 29 years (range 18-85). 30.9% of patients were uninsured or had Medicaid, 83.2% were white, 81.9% received radiation therapy, and 59.9% received chemotherapy. Using univariate analysis, insurance status, radiation, and chemotherapy were statistically associated with OS. Uninsured/Medicaid patients were associated with poorer OS (HR 1.36, 95% CI 1.08-1.71, p < 0.01) compared to those with private insurance. Treatment with radiation therapy (HR 0.43, 95% CI 0.34-0.55, p < 0.01) or chemotherapy (HR 0.51, 95% CI 0.41-0.62, p < 0.01) portended improved OS. After adjusting for age, sex, race, and Charlson-Deyo comorbidity score, statistically significant differences in OS were seen for patients with no insurance/Medicaid. Using multivariate logistic regression, patients with either no insurance or Medicaid were less likely to receive radiation therapy (OR 0.69, 95% CI 0.51-0.95, p = 0.02) compared to patients with private insurance.

CONCLUSION

Using a large national cohort of adult medulloblastoma patients, this study demonstrated the statistically significant disparity of patient outcomes with insurance status. An effort to address healthcare disparity and increase access to cancer care may improve the clinical outcome for adult patients with medulloblastoma.
DISP-09. THE GENOMIC PROFILES AND CLINICAL MANIFESTATIONS OF MENINGIOMAS VARY AMONGST DIFFERENT RACES
Authors: Vetsa Shaurey , Vasandani Sagar , Jalal Muhammad , Yalcin Kanat , Youngblood Mark , Marianayagam Neelan , Elsamadicy Aladine , Qureshi Hanya , Nadar Arushii , Sandhu Mani Ratnesh , Aguilera Stephanie , Mishra-Gorur Ketu , McGuone Declan , Fulbright Robert , Jin Lan , Erson-Omay E Zeynep , Günel Murat , Moliterno Jennifer
Published: November 2022

BACKGROUND

While socioeconomic factors for racial disparities amongst sporadic meningioma patients have been explored, other potential influences are poorly understood. We sought to identify whether the genomic make-up is different amongst meningioma patients of different races and how they correlate with clinical variables.

METHODS

All patients who underwent surgery for sporadic meningioma and consented for whole exome sequencing were eligible. Genomic and clinical data were reviewed and analyzed.

RESULTS

537 intracranial meningiomas from 483 patients with the following racial profile were included: 75% White, 14% Black, 8% Latinx, 3% Asian. Compared with others, Whites were older at the time of diagnosis (p = 0.038) and surgery (p = 0.015). Black and Latinx patients were more likely to present with vision abnormalities (p = 0.006). Whites were more likely to have convexity meningiomas (p = 0.003), while Blacks were more likely to have tumors along the anterior fossa (p = 0.002) with associated somatic Hedgehog (HH) driver mutations (p = 0.008). Both Black and Latinx patients were more likely to have TRAF7 mutated meningiomas (p = 0.006). The highest number of copy number variations was seen in Blacks (p = 0.011) and this correlated with Blacks being more likely to have high-grade tumors, followed by Whites, Asians, and then Latinx (p = 0.020). Black patients trended toward decreased progression-free survival than others (median survival: 57 vs. 130 months; p = 0.06) despite similar extent of resection.

CONCLUSION

Overall, when mutational subgroup and location are considered, Black patients are more likely to have anterior skull base meningiomas with associated visual issues and corresponding somatic HH and TRAF7 mutations. With regards to tumor grade, Blacks harbor more aggressive sporadic meningiomas with a larger prevalence of high-grade meningiomas and associated underlying chromosomal instability compared to others. These findings have implications for meningioma care especially in minority populations, who may harbor more aggressive tumors.
DISP-11. GENDER DISPARITY REGARDING WORK-LIFE BALANCE SATISFACTION AMONG GERMAN NEURO-ONCOLOGISTS: A YOUNGNOA SURVEY
Authors: Kebir Sied , Lazaridis Lazaros , Wick Wolfgang , Platten Michael , Tabatabai Ghazaleh , Combs Stephanie , Schmidt Teresa , Agkatsev Sarina , Blau Tobias , Mäurer Irina , Kahlert Ulf , Sagerer Andre , Berberich Anne , Heider Sina , Müther Michael , Bodensohn Raphael , Behling Felix
Published: November 2022

PURPOSE

Satisfaction with work-life balance (WLB) is an essential factor for persistent motivation of early career researchers. However, WLB satisfaction in the neuro-oncological landscape is not well characterized. We present the results of an interdisciplinary survey focusing on WLB satisfaction among neuro-oncologists in Germany.

METHODS

The questionnaire was sent to 351 physicians, all of whom were members of the Neuro-oncology Working Group “Neuroonkologische Arbeitsgemeinschaft” (NOA) of the German Cancer Society (Deutsche Krebsgesellschaft, DKG). The participants were asked for personal information, individual motivations, scientific interests, activities, individual workload, and job satisfaction. The questionnaire was accessible from 18 March 2021 to 1 April 2021.

RESULTS

Ninety-six physicians (36 female, 60 male) participated in this survey. Age, gender and relationship status were significantly different between participants who were satisfied and those not satisfied with their WLB. Female participants were less likely to be satisfied with their WLB than male participants (25% vs 75%, p = 0.005). In a logistic regression model, the finding that female participants were less likely to be satisfied with their WLB than male participants remained statistically significant (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.21–0.84, p = 0.023) after accounting for possible confounding variables such as age (OR 1.06; 95% CI 1.01–1.11, p = 0.025), childlessness (children available vs not available, OR 0.40; 95% CI 0.10–1.35, p = 0.156), and relationship status (unmarried vs single, OR 2.49; 95% CI 0.50–13.98, p = 0.275; married vs single, OR 6.18; 95% CI 1.29–35.46, p = 0.029).

CONCLUSIONS

This survey demonstrates that WLB satisfaction is significantly decreased among female neuro-oncologists in Germany. It highlights the importance of programs such as “Diversity in Neurooncology” (DivINe), founded by the NOA and aiming to address gender disparities.
DISP-15. TRENDS IN LASER INTERSTITIAL THERMAL THERAPY (LITT): HOW RACE AND SOCIOECONOMIC FACTORS IMPACT ACCESS
Authors: Terrell Danielle , Kandregula Sandeep , Caskey Joshua , Newman Christopher
Published: November 2022

Introduction This study seeks to examine the trends of laser interstitial thermal therapy (LITT) access in the pre-and post-Medicaid expansion time periods; and more specifically, how racial and socioeconomic factors impact access. Methods The National Inpatient Sample (NIS) database was queried for all patients who received LITT from 2010 to 2019 for any indication. Age, gender, race, payer status, and median income by zip code were obtained and compared for the pre-Medicaid expansion (2010-2014), and post-Medicaid expansion (2015-2019) groups. Chi-square analysis was performed for categorical variables, and the student t-test was used to analyze continuous variables. Results The pre-Medicaid expansion (n = 915) and post-Medicaid (n = 3205) time periods were similar in that Whites were the overwhelming majority of LITT recipients (78.7% and 70.8%, p < 0.001). In 2010, all races had low rates of LITT, as would be expected with a new emerging treatment. Although the absolute value of the percentages seems similar, between 2013 and 2014, the proportion of Whites receiving LITT nearly doubled (from 45% to 75%); while all other groups had no significant increase in utilization. Utilization of LITT by Black Americans remained stable, 5.4% and 5.6% in the pre- and post-Medicaid expansion eras, while Hispanics and Others saw slight increases in utilization (8.8% to 10.1% and 7.1% to 13.4% respectively). Although Medicare and Medicaid usage increased over the years, private insurance remained the primary payer for LITT (53.8% and 49.3%, p 0.018). Lastly, patients within the highest income quartiles comprised over half of LITT procedures done in the study period (56.8% and 52.8%, p 0.029). Conclusion Despite nearly a decade and the effects of Medicaid expansion via the Affordable Care Act, LITT is still difficult to access for patients of color, Medicare and Medicaid users, and patients in low-income locales.