bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-18. THE GENOMIC ARCHITECTURE OF GLIOBLASTOMA PREDISPOSITION IS HIGHLY POLYGENIC IN PATIENTS WITH A POSITIVE FAMILY HISTORY OF GLIOMA
Authors: Walsh Kyle , Ostrom Quinn , Byun Jinyoung , Wimberly Courtney , Armstrong Georgina , Amos Christopher ,   GICC Collaborators, Bondy Melissa 
Published: November 2023

Abstract

BACKGROUND
Genetic predisposition to glioblastoma (GBM) is highly polygenic and typically reflects the additive contributions of many common polymorphisms. However, patients with a positive family history of glioma may have a monogenic cancer predisposition syndrome. Such patients would be expected to have reduced contributions from common risk alleles.

METHODS
We sought to compare the polygenic risk of GBM among patients with a confirmed family history of glioma to those with a negative family history. Study subjects included 1628 GBM patients from the GICC study, who completed detailed questionnaires regarding personal and family medical history and underwent genome-wide genotyping of blood-derived DNA on the Illumina OncoArray. Polygenic risk scores were generated based on the 17 independent hits discovered by genome-wide association study (GWAS), with variants weighted by their respective effect sizes.

RESULTS
As expected, polygenic risk scores were significantly higher in GBM patients than in cancer-free control subjects (P=6.6x10-57). A total of 78 GBM patients had a positive family history of glioma, validated by record review. Across strata of family history, we observed that GBM patients with a positive family history of glioma had higher polygenic scores than patients with a negative family history (P=0.039). These results were robust in sensitivity analyses, where each of the 17 contributing variants were excluded from the model, one at a time.

CONCLUSIONS
Polygenic risk scores for GBM are significantly higher in patients with a positive family history of glioma. This suggests that, while family history can be due to rare, penetrant alleles, a large contingent of familial GBM may arise in families with a heavy polygenic burden of GBM risk alleles. Strategies for rare variant discovery might consider a two-pronged approach of sequencing kindreds with multiple affected members, as well as solitary GBM diagnoses in patients that have low polygenic risk scores.
EPID-24. CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT
Authors: Price Mackenzie , Neff Corey , Kruchko Carol , Waite Kristin , Cioffi Gino , Barnholtz-Sloan Jill , Cordeiro Brittany , Penas-Prado Marta , Ozer Byram , Cimino Patrick , Gilbert Mark , Armstrong Terri , Ostrom Quinn 
Published: November 2023

Abstract

BACKGROUND
Incidence, prevalence, and survival are population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) specializes in research of 12 rare CNS tumor types to improve approaches to care and treatment. These tumors include atypical teratoid/rhabdoid tumors, brainstem and midline glioma, choroid plexus tumors, ependymoma, high grade meningioma, gliomatosis cerebri, medulloblastoma, oligodendroglioma/anaplastic oligodendroglioma, pineal region tumors, pleomorphic xanthoastrocytoma, CNS embryonal tumors, not elsewhere classified (NEC)/not otherwise specified (NOS), and primary CNS sarcoma. This study aimed to update incidence, prevalence, and survival statistics for these tumors.

METHODS
The Central Brain Tumor Registry of the United States (CBTRUS) database, a combined dataset of CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology and End

RESULTS
(SEER) data, was used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race-ethnicity, and age (2008-2019). NPCR data were used to calculate relative survival (RS) estimates (2008-2018). Prevalence on December 31, 2019 was estimated using annual age-specific incidence and survival from CBTRUS and SEER, respectively.

RESULTS
AAAIR was 1.51 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR=0.41/100,000). Most tumor types were more common in males, adults (ages 40+ years) or children ages &lt; 15 years, and non-Hispanic White individuals. Ependymomas were most prevalent (19,339 cases) followed by oligodendrogliomas (15,070 cases). RS for all subtypes combined at 1-, 5-, and 10-years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (5-years=90.6%) and primary CNS sarcomas had the lowest RS (5-years=7.7%).

CONCLUSIONS
Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population-based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.
EPID-26. THE IMPACT OF COVID-19 POSITIVITY AND PREVALENCE ON TREATMENT UTILIZATION FOR GLIOBLASTOMA PATIENTS
Authors: Zhu Ping , Chen Clark ,   NC Consortium
Published: November 2023

Abstract

OBJECTIVES
Glioblastoma (GBM) is the most common (46.1%) and aggressive malignant primary brain tumor. We propose to explore the pandemic effect on the change of health care delivery for glioblastoma patients using the National Cancer Database (NCDB) and validate the findings in primary brain tumors using one of the largest COVID-19 real-time centralized data in the world - the National COVID Cohort Collaborative (N3C) database.

METHODS
Multivariable binary logistic regression models were performed to investigate whether the pandemic (including COVID-19 positivity and density of COVID-19 prevalence based on zip code-level) affected the receipt of GBM care including surgical procedure, radiation, and chemotherapy.

RESULTS
A total of 4093 GBM patients and 4481 primary brain tumor patients were derived from the NCDB and N3C, respectively. Seventy-nine percent of GBM patients received the COVID-19 test (3241/4093) and 290 patients were COVID-19 positive. Black, Hispanic, lower education-level, and higher Charlson/Deyo Score ( &gt;=2) were significant factors related to COVID-19 positivity. The proportions of receiving GBM care significantly decreased in COVID-19-positive patients compared to pre-pandemic years (2018-2019). After adjusting the potential confounders and covariates, the odds of undergoing tumor resection/biopsy (aOR-0.37, p&lt; 0.001), radiation (aOR-0.36, p&lt; 0.001), and chemotherapy (aOR-0.31, p&lt; 0.001) for COVID-19 positive patients were significantly lower than COVID-19 negative patients (NCDB). Similar results were detected in primary brain tumor patients using N3C. The odds of undergoing surgical procedures in patients resided in the higher density of COVID-19 prevalence (four zip code-level, per 1000 population) (aOR-0.63, 0.69, 0.59, all p&lt; 0.001) and with COVID-19 positivity (aOR-0.54, p&lt; 0.001) were significantly lower comparing to the related reference groups (N3C).

CONCLUSIONS
Our findings suggest that healthcare delivery for GBM and primary brain tumors has been remarkably affected by COVID-19 positivity and high-level COVID-19 prevalence during the pandemic.
EPID-32. A COST ANALYSIS OF BRAIN AND NERVOUS SYSTEM CANCER CARE: AN EXAMINATION OF HEALTHCARE EXPENDITURE TRENDS IN THE UNITED STATES FROM 1996 TO 2016
Authors: Guo Edward , Gupta Mehul , Rossong Heather , Ahmed Shubidito , Stukalin Igor , Lama Sanju , Sutherland Garnette 
Published: November 2023

Abstract

INTRODUCTION
Management of brain and central nervous system malignancies is associated with substantial healthcare spending, yet estimates of per-patient cost and longitudinal temporal trends remain elusive. In this study, we investigate trends in United States (US) healthcare spending on these diseases between 1996-2016.

METHODS
We utilize inflation-adjusted national healthcare spending data and age-adjusted prevalence estimates from the Institute for Health Metrics and Evaluation to estimate per-patient US healthcare spending stratified by age and care setting. We employ joinpoint regression to identify temporal trends in healthcare spending, expressed as annual percent change (APC). Drivers of change data from 1996-2013 were evaluated to investigate shifts associated with increased spending.

RESULTS
In 2016, total healthcare spending attributable to brain and nervous system cancers was $6.85 billion (95% CI, $5.98-7.57 billion), corresponding to $2,245 (95% CI $1,962-$2,480) per patient, with the largest share coming from inpatient care settings ($4.60 billion [95% CI 3.87-5.24 billion]). Private payers shouldered the majority of costs (65.6%) compared to public payers (28.1%) and out-of-pocket expenses (6.4%). The average APC in spending between 1996-2016 was 3.69% [95% CI 3.00%-4.39%], driven primarily by an increase in the price and intensity of inpatient care (11.8% [95% CI 7.7%-16.1%). Further, three statistically significant periods of spending change were identified: 1996-2005 (2.42% [95% CI 2.04-2.80%], p &lt; 0.001 ), 2005-2008 (4.43% [95% CI 1.08%-7.89%], p &lt; 0.0001), 2008-2014 (6.32% [95% CI 5.41%-7.25%], p &lt; 0.001), with spending being relatively stable from 2014-2016.

DISCUSSION
US expenditures for brain and nervous system malignancies are substantial and have significantly increased between 1996-2016, largely driven by increased inpatient spending. These findings may inform policy efforts to reduce the disease burden while balancing healthcare spending.
EPCO-02. DNA METHYLATION PROFILING OF BRAIN METASTASIS REVEALS UNDERLING TUMOR RECURRENCE SIGNAL AND ASSOCIATED PATHWAYS
Authors: Ajisebutu Andrew , Sosa Julio , Zuccato Jeffery , Liu Jeff , Patil Vikas , Zadeh Gelareh 
Published: November 2023

Abstract

INTRODUCTION
Brain metastases, the most common form of intracranial neoplasms, carry a poor survival rate, mostly attributed to their high recurrence rates. Currently there are no reliable methods to determine which patients will progress. DNA methylation profiling (DNAmp) has become a useful tool in the diagnosis and stratification of intracranial neoplasms, and has the potential to provide clues on the epigenetic mechanisms that govern tumor behavior.

METHODS
A cohort of 58 BM tumor samples were selected for analysis. The cohort was composed of three groups: N=21 primary metastatic tumors (PMT), N=21 matched paired recurrent tumors (RMT), and a cohort of N= 16 primary metastatic tumors without any evidence of recurrence (NRMT). All tumor samples underwent DNAmp on the Illumina Infinium EPIC array to determine their methylation status at 850,000 CpG sites. Tumors were profiled via unsupervised hierarchical clustering, pathway enrichment analysis, and cell deconvolution analysis.

RESULTS
Differential methylation analysis revealed over 32617 differentially methylated CpG sites between grouped PMT and RMT samples, and 835424 sites between PMT and NRMT samples. When comparing PMT with NRMT samples, we revealed a distinct DNAmp that was upheld upon hierarchical clustering analysis. NRMT samples show a significant downregulation of pathways involved in DNA-binding and transcriptional regulation. Paired analysis of PMT and RMT revealed a relative paucity of differentially methylated CpG sites shared across paired samples: a total of 257 probes were differentially methylated across 14/19 samples. These probes however showed enrichment primarily for DNA-binding and transcription factor regulation, in reverse from the non-recurrent samples.

CONCLUSION
Our data suggests that DNAmp may be capable of differentiating tumors destined to progress from those with less aggressive features, and that DNAmp appear to remain stable through to recurrence. This work demonstrates the potential for DNA methylation to be utilized to uncover pathways associated with BM recurrence.
EPCO-03. A COMPREHENSIVE SINGLE-CELL ATLAS OF SCHWANNOMA REVEALS CONSERVED CELLULAR STATES ACROSS DIFFERENT GENETIC BACKGROUNDS AND ANATOMIC LOCATIONS
Authors: Castro Luis Nicolas Gonzalez , Gavish Avishai , Bussema Lillian , Neftel Cyril , Nomura Masashi , Chiocca E Antonio , Bi Wenya Linda , Arnaout Omar , Barker Frederick , Brown Justin , Jordan Justin T , Stemmer-Rachamimov Anat , Plotkin Scott R , Tirosh Itay , Suva Mario 
Published: November 2023

Abstract

BACKGROUND
Despite being associated with molecular alterations in the NF2 gene, there is limited understanding of the gene expression programs that govern the behavior of schwannomas both in sporadic cases as well as in patients with schwannoma predisposition syndromes, and also with respect to their anatomic location.

METHODS
We characterized the transcriptional heterogeneity of schwannomas across different genetic backgrounds and anatomic locations at the single-cell level. Tumor samples from patients undergoing resection for symptomatic schwannoma were dissociated and single cells were processed for full-transcript whole transcriptome profiling via Smart-seq2. Our cohort of 22 schwannomas, includes 5 tumors from schwannomatosis patients, 11 tumors from neurofibromatosis type 2 patients, and 6 sporadic tumors – 3 of which had grown after radiation treatment. Anatomically, 12 tumors were excised from cranial nerves (11 vestibular, 1 accessory) and 10 from spinal and other peripheral nerves.

RESULTS
We profiled 11,373 cells, including 4725 neoplastic cells, 2425 fibroblasts, 1314 T cells, 1258 endothelial cells, 969 myeloid cells, 503 pericytes and 240 Schwann cells. Copy number alteration analyses reveal evidence of intratumoral polyclonality (supporting the hypothesis of multiple sites of origin for a tumor). Using non-negative matrix factorization, we identify 6 distinct transcriptional metaprograms, with gene signatures related to stress, myelin production, antigen presentation, interferon signaling, glycolysis and extracellular matrix. After comparison with a pan-cancer gene expression dataset, we note unique interferon and antigen presentation metaprograms in schwannoma, with the latter being mainly characterized by expression of MHC Class II genes. Overall, we observe conserved expression of these metaprograms across anatomic locations and genetic backgrounds, with the exception of decreased interferon signaling for vestibular tumors.

CONCLUSION
We provide a comprehensive single-cell characterization of schwannoma spanning diverse genetic and anatomic backgrounds. We describe unique transcriptional metaprograms for antigen presentation and interferon signaling, which might underlie mechanisms for immune evasion.
EPCO-08. CONVERGENCE OF NON-CODING SOMATIC MUTATIONS ON CANCER DRIVER PLEXUSES IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Chen Tina Huey-Miin , Singhal Divya , Gallo Marco 
Published: November 2023

Abstract
Central nervous system tumors are the most common pediatric malignancies after leukemia, and the most common cause of cancer death among persons ages 0 – 14 [1,2]. Despite its low incidence rate, pediatric high-grade gliomas (pHGGs) account for over 40% of all childhood brain tumor deaths [3, 4]. As such, it remains the focus of many research teams across the globe. The discovery of recurrent mutations in genes encoding histone H3.3 [5] was a breakthrough in the genetic basis of pHGGs and highlighted the relevance of epigenetic reconfiguration for oncogene activation. However, much work is still needed to uncover driver alterations responsible for tumor initiation or progression. pHGGs have frequent epigenetic dysregulation [6,7] and abundant somatic mutations in the noncoding regions of the genome [8], but the functional relevance of the noncoding somatic mutations has not been evaluated systematically. Here, we assess correlations between noncoding somatic mutations in pediatric brain-specific cis-regulatory elements (CREs) and changes in gene expression. We demonstrate the sparsity of recurrent mutations in CREs. Then illustrate the power of graph database in consolidating multi-omics datasets for efficient queries. Our network approach for charting the genomic, epigenetic, and transcriptomic landscape of pHGG allow us to 1) identify clusters of CREs associated with dysregulated gene expression, 2) nominate transcription factors whose binding affinities are recurrently impacted by somatic mutations found in pHGGs, and 3) establish regulatory networks potentially guiding pHGG tumor growth and progression.
EPCO-18. HETEROCHROMATIN DYSFUNCTION IMPACTING GENOMIC TOPOLOGY AND SUPERENHANCER LANDSCAPES PROMOTES ATRX-DEFICIENT GLIOMAGENESIS
Authors: Malgulwar Prit Benny , Saw Ajay Kumar , Singh Anand , Danussi Carla , Dharmaiah Sharvari , Johnson William E , Rai Kunal , Huse Jason 
Published: November 2023

Abstract
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in diffuse gliomas. Whether and how ATRX deficiency promotes oncogenesis remains unclear, despite its implication across a broad array of physiological processes. We sought to delineate the molecular mechanisms by which global epigenomic dysfunction promotes oncogenic phenotypes in ATRX-deficient glioma models. Building on earlier work implicating chromatin accessibility and transcriptional shifts, we employed integrated epigenomic profiling in Atrx-intact and -deficient murine neuroepithelial progenitor cells (mNPCs), validating findings will functional approaches in human glioma stem cells (GSCs) of appropriate genotype. We found that ATRX deficiency dramatically impacted the integrity of large heterochromatin domains genome-wide, with tangible effects on underlying gene expression. This process fundamentally altered chromatin topology, as assessed by Hi-C analysis, and associated superenhancer landscapes, influencing key developmental gene sets like the HOXA cluster. Pharmacological inhibition of HOXA signaling in GSCs selectively reduced proliferation, increased apoptosis, and impaired in vivo growth in the ATRX-deficient context. Finally, our results pointed to derepression of LINE1 endogenous retroviral elements as key mediators of ATRX-deficient heterochromatin dysfunction. Our work implicates novel and targetable molecular mechanisms involving complex epigenomic rewiring and chromatin topology in ATRX-deficient oncogenesis. In doing so, we advance the understanding of a deadly brain tumor along with broader conceptions of epigenetic mechanisms as fundamental drivers in cancer.
EPCO-21. IDENTIFYING FACTORS THAT PREDICT GENETIC PREDISPOSITION TO BRAIN TUMOR FORMATION
Authors: Lee John , Tripathy Arushi , Guivatchian Tannaz , Koeppe Erika , Stoffel Elena , Al-Holou Wajd 
Published: November 2023

Abstract

INTRODUCTION
Increasing evidence suggests that glioma formation may have a greater hereditary component than initially thought. Identification of individuals with a genetic predisposition is critical for appropriate monitoring and treatment.

OBJECTIVE
To analyze the personal and family histories of patients with intrinsic brain tumors seen in a cancer genetics clinic to inform referral practices.

METHODS
A prospective database of cancer genetics data from a large multidisciplinary cancer genetics clinic was queried for brain tumors from 2007-2023. Genetic test results, age of brain cancer diagnosis, number/types of distinct cancers, oncologic family history, and personal and family history of cancer syndromes were recorded. Fisher’s exact tests and ANOVA were used for analysis.

RESULTS
Sixty-five patients with intrinsic brain tumors, which included 53 high and low grade gliomas, were identified. There were 33 males; the mean age of diagnosis was 34.6±23.4. Fifty-three (81.5%) had genetic testing performed. Of these, 19 (35.8%) were found to have germline pathogenic variants (PV), 10 (18.9%) had variants of unknown significance (VUS), and 24 (45.3%) were found to have no mutations. Patients with PVs were younger than patients with normal genetic screening (28.1 vs 41.5 years, p= 0.06), and patients with either PV or VUS were significantly younger (p= 0.04) than patients with normal screening. Regarding personal cancer history, patients with and without PVs had a similar history of personal cancers (p= 0.20). Regarding family history, only 1 patient with PV had a family history of brain cancer compared to 15 in patients with negative testing (5.3% vs 44.1%, p= 0.004).

CONCLUSIONS
Only younger age at presentation was identified as a predictor of a PV or VUS. A lack of personal/family history of cancer does not preclude a genetic predisposition to cancer. We recommend that younger patients with intrinsic brain tumors should be referred for genetic testing.
EPCO-22. LONGITUDINAL MOLECULAR CHARACTERIZATION IDENTIFIES TREATMENT DRIVEN EVOLUTION OF OLIGODENDROGLIOMA
Authors: Chowdhury Tamrin , Johnson Kevin , Kocakavuk Emre , Heo Chaewon , Ye Gordon Y , Ghospurkar Padmaja , Wade Taylor , Barnholtz-Sloan Jill , Costello Joseph , Elliott Carol , French Pim , Golebiewska Anna , Hermes Beth , Hong Chibo , Horbinski Craig , Khasraw Mustafa , LaViolette Peter , Li Kay Ka-Wai , Lipp Eric , Lowman Allison , McCortney Katy , Moon Hyo-Eun , Ng Ho-Keung , Padovan Marta , Paek Sun Ha , Vallentgoed Wies , Vaubel Rachael , Wesseling Pieter , Westcott Kerryn ,   GLASS Consortium, Varn Frederick , Verhaak Roel 
Published: November 2023

Abstract
Oligodendroglioma is characterized by oligodendrocyte-like histology, mutation in the IDH genes, along with codeletion of chromosome arms 1p and 19q. Treatment for oligodendrogliomas combines surgery, followed by observation, and chemotherapy and/or radiotherapy when tumors progress. Most oligodendrogliomas eventually recur with a more aggressive phenotype, leading to patient mortality but molecular mechanisms remain poorly understood. To investigate the molecular trajectory of oligodendroglioma, we collected more than 270 longitudinal samples from over 130 oligodendroglioma patients, to perform whole genome or whole exome sequencing, bulk RNA, and single-nucleus RNA sequencing (n = 30 samples). Common mutations in IDH1/2, TERT promoter, CIC, and FUBP1 were observed. About half of the CIC and FUBP1 mutations occurred in the initial sample and persisted stably throughout recurrence. The majority of PIK3CA and PIK3R1 mutations were either shared or present in recurrences only implicating the PI3K pathway in oligodendroglioma recurrence. Mutational signature analysis revealed 34.5% of tumors treated with alkylating agents acquired SBS11/SBS31 associated hypermutation. By integrating signatures with clonality estimates, we approximated the timing of mutational processes and found that clonal timings of treatment related mutations correlate with the treatment administration date. We found that aging signature-related mutations were mostly clonal, and treatment signature-related mutations were more likely to be sub-clonal, supporting the late emergence of these mutations following treatment. We observed increased somatic copy number alterations in oligodendroglioma recurrences, reflected in notable chromosome 4 losses. Associating treatment with snRNAseq derived cellular states, we observed a significant increase in the fraction of proliferating stem-like cells in the hypermutator versus non-hypermutator recurrent samples. These findings shed light on the molecular changes occurring in oligodendrogliomas following treatment and provide insights that may aid in targeting treatment resistance.