bluuebunny/crossref_metadata_2025_split huggingface dataset:
GENE-23. GENOME-WIDE DNA METHYLATION PROFILES DISTINGUISH SILENT FROM NON-SILENT ACTH ADENOMAS
Authors: Ricklefs Franz , Fita Krys , Rotermund Roman , Westphal Manfred , Schüller Ulrich , Flitsch Joerg 
Published: November 2019

Abstract
BACKGROUND Corticotroph adenomas are immunopositive for adrenocorticotrophic hormone (ACTH) associated with elevated blood ACTH levels leading to Cushing disease (CD). Yet silent ACTH adenomas (SCA) immunostain for ACTH but do not cause hypercortisolism. SCA have consistently been shown to have a more aggressive postoperative course, then nonfunctioning and ACTH adenomas. Here we show that genome-wide methylation profiles can be used to distinguish ACTH adenomas from SCA. METHODS16 SCA patients and 19 CD patients that underwent transsphenoidal resection were included. Tumor size was measured by MRI. Tumor histology was proven by immunstain for ACTH and routine histopathology. Sanger sequencing was performed to analyse mutational burden within the ACTH locus (n=3). Genome-wide DNA methylation profiling was performed using a 850k Illumina EPIC array and classified by the DKFZ brain tumor classifier as well as PCA analysis using R (n=17). RESULTS Mean age was 55,4 and 46,2 for SCA and CD patients, respectively. Patients with SCA had significantly larger tumors (SCA: 12,56±3,07ccm; CD: 1,9±1,2ccm p< 0.01). Both SCA and CD tumors showed strong expression of ACTH as proven by immunohistochemistry. Sanger sequencing revealed no mutations within the ACTH gene locus in SCA. Both, SCA and CD tumors classified as ACTH adenomas by genome-wide methylation profiling. Further PCA of DNA methylation profiles allowed subtype tumor classification into SCA and CD adenomas. CONCLUSION SCA show a strong expression of ACTH without causing hypercortisolism. The reason for this is not yet known. Our data suggest that SCA do not harbor specific mutations within the ACTH gene locus. However genome wide methylation profiles allows subgrouping of SCA and CD adenomas.
GENE-25. GWAS BY MOLECULAR SUBTYPE IDENTIFIED NOVEL RISK LOCI FOR ADULT DIFFUSE GLIOMA
Authors: Eckel-Passow Jeanette , Decker Paul , Kosel Matthew , Kollmeyer Thomas , Molinaro Annette , Rice Terri , Drucker Kristen , Hansen Helen , McCoy Lucie , Bracci Paige , Wiemels Joseph , Wiencke John , Lachance Daniel , Wrensch Margaret , Jenkins Robert 
Published: November 2019

Abstract
Genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with adult diffuse glioma development. These regions were identified by performing GWAS of glioma overall and GWAS by pathology (GBM and nonGBM). Subsequently, these regions have been evaluated for associations with specific molecular subtypes. The 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly-classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. TERT promoter mutation has also been shown to be associated with age at diagnosis and patient outcome. We hypothesized that germline variants may increase susceptibility to, or interact with, these somatic alterations to accelerate the development of specific molecular subtypes of glioma. To test our hypothesis, we performed a GWAS by glioma molecular subtype – as defined by presence or absence of IDH and TERT somatic mutation and 1p/19q codeletion – utilizing a two-stage design and subsequent meta analysis that included 3001 total glioma cases and 2697 total controls. Data were imputed using the Michigan Server and logistic regression was used, adjusting for age and sex. The Cancer Genome Atlas (TCGA) data were used to perform an expression quantitative trait loci (eQTL) analysis on candidate germline variants. Variants in 2q37 and 7p22 were associated with IDH-mutated glioma (meta analysis p< 5x10-8). The eQTL analyses demonstrated significant associations between 2q37 variants and expression of nearby genes as well as associations between 7p22 variants and nearby genes (p< 0.0001). In conclusion, we identified and validated novel germline variants in two genes that are associated with etiology of IDH-mutated adult diffuse glioma.
GENE-26. HOST GENETIC VARIATIONS IN MACROPHAGE MIGRATION INHIBITOR FACTOR CONFER WORSE PROGNOSIS IN GLIOBLASTOMA
Authors: Otvos Balint , Grabowski Matthew , Alban Tyler , Golubovsky Joshua , Neumann Chase , Rabjlenovic Anja , Bayik Defne , Lauko Adam , Bucala Richard , Vogelbaum Michael , Lathia Justin 
Published: November 2019

Abstract
Genetic and systemic prognostic factors have been identified in glioblastoma (GBM) that correlate with survival, but patient-specific genomic risk factors that impact prognosis or response to immunotherapies have not been elucidated. GBM promotes an immune suppressive microenvironment via many mechanisms including the production of macrophage migration inhibitory factor (MIF) by GBM cancer stem cells, which activates myeloid derived suppressor cells (MDSCs). Increased circulating and intracranial MDSCs as well as intratumoral MIF expression in GBM patients portend a worse overall prognosis. Endogenous MIF expression is dependent on two genetic microsatellite loci: single nucleotide polymorphisms (SNPs) and CATT repeats within the promoter. To determine whether these genetic variations were linked to GBM development and/or prognosis, we assessed peripheral nucleated blood from 520 GBM patients for the MIF SNPs and CATT repeats. MIF microsatellite frequencies were similar between the normal population and GBM patients indicating loci variability was not a risk factor for GBM development. However, newly diagnosed IDH wild-type GBM patients with a minor allele SNP who received standard of care therapy had a 3.1 month shorter progression free survival (PFS), and a 4.3 month shorter overall survival (OS) when compared to patients with two major allele SNPs. This association was seen also with the CATT-repeat analyses. Furthermore, in a multivariate analysis for PFS that included age, sex, Karnofsky performance status, MGMT methylation status, 1p/19q co-deletion, and SNP status as covariates, only age and SNP status were independently associated with shorter PFS. Taken together, patients with variant MIF microsatellite loci experienced shorter PFS and decreased OS compared to those with the most common loci. These results are currently being validated in a separate 1700 patient cohort with the intent of understanding how MIF expression influences myeloid populations within the GBM microenvironment and then developing novel peripheral GBM screening markers for aggressiveness.
GENE-27. MENINGIOMA RECURRENCE: ROLE OF M1/M2 TUMOUR-ASSOCIATED MACROPHAGE INFILTRATION
Authors: Proctor Dustin , Huang Jordan , Lama Sanju , Albakr Abdulrahman , Van Marle Guido , Sutherland Garnette 
Published: November 2019

Abstract

BACKGROUND
Meningioma, a most common brain tumour, has a high rate of recurrence. Tumour-associated macrophages (TAMs) are the most abundant immune cell type in meningioma. TAMs display functional phenotypic diversity and may establish either an inflammatory and anti-tumoural or an immunosuppressive and pro-tumoural microenvironment. TAM subtypes present in meningioma and potential contribution to growth and recurrence is unknown.

METHODS
Fluorescence immunohistochemistry was used to evaluate the distribution and quantify M1 and M2 TAM populations in 30 meningioma tissues. Association between quantified M1 and M2 cells and M1/M2 ratio to tumour characteristics including WHO grade, tumour recurrence, size, location, peri-tumoural edema and patient demographics such as age and sex was examined.

RESULTS
TAM cells accounted for ~17% of all cells in tumour tissues. Importantly, greater than 80% of infiltrating TAMs were discovered to be of a polarized pro-tumoural M2 phenotype which positively associated with tumour size. TAM subtype profiles differed significantly between non-recurrent (n=18) and recurrent meningioma (n=12) (P=0.044). Specifically, the M1/M2 cell ratio was decreased by ~250% in recurrent tumours.

CONCLUSION
This study is the first to confirm existence of pro-tumoural M2 TAMs in the meningioma microenvironment and a potential role in tumour growth and recurrence.
GENE-30. PRELIMINARY STUDY ON WHOLE-EXOME SEQUENCING TECHNOLOGY IN THE GENETIC ANALYSIS OF PEDIATRIC PATIENTS WITH GLIOMAS
Authors: Lai Mingyao , Li Juan , Zhen Junjie , zhou jiangfen , Hu Qingjun , ye Minting , Li Shaoqun , Wang Lichao , Zhou Cheng , Zhou Zhaoming , Cai Linbo 
Published: November 2019

Abstract

OBJECTIVE
To analyze the genes related to the signaling pathways in pediatric gliomas and drug-related genes with whole-exome sequencing technology.

METHODS
The tumor tissues and matched blood samples of 17 enrolled patients were detected with whole-exome sequencing technology. There were 3 cases of diffuse midline gliomas, 2 cases of childhood glioblastomas, 3 cases of disffuse astrocytoma, 1 case of pleomorphic xanthoastrocytoma, 1 case of ganglioglioma, 6 cases of anaplastic ependymoma and 1 case of ependymoma in this study. All the enrolled patients who were no more than 14 years old received surgery in the Department of Neurosurgery, Guangdong Sanjiu Brain Hospital. The diagnosis was confirmed by pathological examination and the sample acquisition was approved by hospital ethics committee.

RESULTS
With the use of whole-exome sequencing technology, a total of 31 related genetic mutations were detected in 15 cases, while no genetic mutation was detected in the other 2 cases. The genes related to the signaling pathways in pediatric gliomas included ATRX, ASL1, BCOR, EP300, FGFR1, H3F3A, IGF1R, MED12, PIK3R1, PRKDC, RB1, SETD2, SMARCA4, SOX2, TGFBR2, and the drug-related genes included AKT1, BCL2, BRAF, BRCA2, CCND1, CCND2, CDK6, EGFR, FGF3, KRAS, MET, PDGFRA, PIK3CA, PTEN, TP53, TSC1. One patient only had genes related to the signaling pathways, and 14 patients had drug-related genes.

CONCLUSION
Applying whole-exome sequencing technology in the genetic analysis of pediatric patients with gliomas has remarkable guiding significance for revealing the mechanism of disease, searching for therapeutic targets and adopting individualized treatment, which can bring potential benefits to pediatric patients. However, more samples and further data analysis and verification are needed in future study.
GENE-36. INTEGRATING TRANSCRIPTOMICS AND KINOMICS IDENTIFIES SYNERGISTIC DRUG COMBINATIONS FOR GLIOBLASTOMA TREATMENT
Authors: Jermakowicz Anna , Stathias Vasileios , Suter Robert , Duncan James , Schürer Stephan , Ayad Nagi 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and malignant adult brain tumor. Despite years of research, few advancements have been made in its management. One promising avenue of research has been treatment with BRD4 inhibitors, which decrease oncogene expression in GBM cells. However, resistance to these inhibitors is rapidly acquired. Kinome reprogramming is thought to underlie this resistance, suggesting a need for combination therapy with kinase inhibitors. The goal of this study is to determine whether transcriptomic and kinomic profiling of GBM tumors will identify synergistic drug pairs for GBM treatment. We profiled the active kinome on a set of three newly-diagnosed GBM patient-derived xenograft (PDX) tumors and three recurrent tumors using quantitative SILAC mass spectrometry. Additionally, kinome reprogramming following BET inhibition was profiled in vitro using the BET inhibitor JQ1. Kinome activity was uploaded into our novel computational platform, SynergySeq, to assess the synergistic potential of kinase inhibitors with JQ1. Additionally, single cell RNA-sequencing of a GBM tumor was used to determine the cell populations affected by each inhibitor. To quantify synergy in response to combination therapy, cells were treated with a combination matrix of JQ1 and a kinase inhibitor in variable concentrations and cell death was quantified via ATP levels. Our results showed that newly-diagnosed tumors were predicted to be sensitive to combined BET inhibition with Bcr/Abl, EGFR, and FGFR kinase inhibitors. Recurrent tumors were sensitive to combined Bcr/Abl and FGFR inhibitors but were not sensitive to EGFR inhibitors. We screened inhibitors in vitro and found a synergistic effect for the combination of JQ1 and TAS120, a pan-FGFR inhibitor. These data suggest that clinically a brain penetrant BET inhibitor should be effective in combination with a brain penetrant FGFR inhibitor. Importantly, our computational platform is a novel informatics-based approach for targeted therapy in a patient-specific and disease-specific manner.
GENE-40. CHARACTERIZING EPIGENETIC INTRATUMORAL HETEROGENEITY IN GLIOMA USING SINGLE-CELL BISULFITE SEQUENCING
Authors: Johnson Kevin C , Anderson Kevin , Courtois Elise , Barthel Floris , Samuels Michael , Robson Paul , Bulsara Ketan , Das Sunit , Verhaak Roel 
Published: November 2019

Abstract
Genetic and epigenetic alterations contribute to the observed intratumoral heterogeneity in adult glioma. Current glioma classification, based on genotype (e.g., IDH1 mutations) and DNA methylation profiles (e.g., glioma CpG Island Methylator Phenotype), can provide clinically relevant tumor subgroups. However, traditional bulk sampling fails to adequately capture the full complement of epigenomic heterogeneity, and may mask deadly features present in less abundant glioma cells. To more precisely characterize the glioma epigenome, we separately profiled single-cell DNA methylation (Reduced Representation Bisulfite Sequencing, RRBS), single-cell RNA expression (10X genomics), and bulk whole genome sequencing in nine gliomas. The genomic regions profiled by scRRBS were primarily gene promoters, but adequate coverage was also reached for glioma-specific enhancer elements and binding sites of chromatin remodelers. Unsupervised clustering of single-cell DNA methylation data revealed intratumoral variability in epigenetic classification and these cell types were distinguished by regulatory element DNA methylation. We further integrated single-cell epigenetic, single-cell transcriptomic, and genomic features to better understand gene regulation and reconstruct each tumor’s lineage history. Together, our study aims to generate a glioma cellular hierarchy shaped by the epigenetic programs that drive tumor growth.
GENE-41. UNDERSTANDING THE DIFFERENCES IN ADOLESCENT AND YOUNG ADULT (AYA) GLIOMAS AND OLDER ADULT (OA) GLIOMAS BASED ON FUNCTIONAL MOLECULAR SUBGROUPS
Authors: Bi Catherine , Subramaniam Ashwin , Xiu Joanne , Heimberger Amy , Michelhaugh Sharon , Mittal Sandeep , Sumrall Ashley , Subramaniam Deepa 
Published: November 2019

Abstract

BACKGROUND
Gliomas in the AYA population (15–39 years of age) have unique biological characteristics and need to be better characterized.

METHODS
Glioma tumors in AYA subjects and subjects >65 years of age (OA) were analyzed by next generation sequencing using a 592 gene panel. Pathogenic mutations were classified into five functional groups, viz. metabolic pathways genes (IDH1/2, FH), tumor suppressor genes (TP53, RB1, APC, NF1/2, PTEN, TSC1/2), genes involved in DNA repair (MMR genes, BRCA1/2, POLE, ARID1A, CHEK2, ATM, BLM, BRIP1, WRN, BARD1, POT1, MUTYH), oncogenes (BRAF, NRAS, HRAS, EGFR, PDGFRA, FGFR1, NOTCH1, MYCN), and genes involved in transcriptional regulation (SETD2, H3F3A, KMTD2A/2C/2D, KDM6A, PIK3CA). Mutation frequency in AYA tumors and OA tumors were compared using Chi-squared analysis (Pearson’s score χ2; likelihood ratio LR).

RESULTS
720 unique gliomas tumors were analyzed: 118 AYA, 602 OA; 420 males, 300 females. When both groups are considered together, glioblastoma was the most common histology (75%), followed by grade 3 astrocytoma (13%), glioma NOS (3.8%), oligodendrogliomas (3%), low grade gliomas (2.9%) and other (2.3%). AYA tumors harbored more metabolic pathway gene mutations (χ2 137.7, p< 0.0001) driven primarily by IDH1 mutations, while OA tumors had a higher mutation frequency in oncogenes (χ2 9.22, p=0.0024) driven by EGFR mutations (LR 27.567) and tumor suppressor genes (χ2 40.35, p< 0.0001) driven by NF1 (LR 18.147) and PTEN (LR 66.216). No significant differences were noted in mutation frequency in DNA repair or transcriptional regulation genes. However, AYA glioblastoma tumors had a significant increase in mutations in genes involved in chromatin remodeling, (χ2 11.43, p=0.0007) even after excluding H3F3A.

CONCLUSIONS
Functional genomic classification of AYA tumors may help develop better targeted therapies, especially focused on genes involved in metabolic pathways and transcriptional regulation.
GENE-54. INVESTIGATING THE ROLES OF NCOR1 AND NCOR2 IN METASTATIC INVASION INTO THE SPINE
Authors: Sultan Zain , Rocco Sabrina , Szerlip Nicholas , Calinescu Alexandra 
Published: November 2019

Abstract
Anywhere from 30–70% of osseous metastatic disease occurs in the spine across many different tumor types. These metastases lead to debilitating pain and neurologic dysfunction significantly reducing patients’ quality of life. Unfortunately, the cause of preferential metastatic growth to the spine is not understood. The purpose of this study was to identify the role of NCOR1 and NCOR2/SMRT, genes included in Cancer Gene Census (https://cancer.sanger.ac.uk/cosmic), in the promotion of metastatic spread to the spine. NCOR1, located on chromosome 17, and NCOR2, located on chromosome 12, encode for proteins that mediate ligand-independent transcription repression by forming a complex that activates HDAC3. Studies have shown that low expression of NCOR1 and NCOR2 is associated with decreased median survival in some cancers. Our lab collected tumors and blood/bone marrow samples from 9 patients with different primary tumors that metastasized to the spine, and sequenced their DNA. Based on preliminary bioinformatics analysis, we discovered a substitution of thymine to cytosine at chr17:16165160 in the NCOR1 sequence, which results in a nonsense mutation that ends transcription in the second exon. After Sanger sequencing validation, this mutation was found to be present in both the tumor and control samples of all patients, resulting in two possible interpretations: a germline mutation of NCOR1 sequence or the presence of tumors cells in the blood. In addition, by bioinformatics analysis, we identified a substitution of cytosine to thymine at chr12:124341916 in exon 34 of the NCOR2 sequence, resulting in a missense mutation that changes an alanine to threonine. Further experimentation must be done to determine the role of NCOR1 and NCOR2 in metastatic spread to the spine. The hope is to identify targetable molecules and pathways for the design of novel therapies aimed to improve the outcome of these patients.
HOUT-07. ASSOCIATION BETWEEN BASELINE BODY MASS INDEX (BMI) AND OUTCOMES FOR PATIENTS WITH GLIOBLASTOMA
Authors: Chew Jessica , Morin Olivier , Braunstein Steve 
Published: November 2019

Abstract

OBJECTIVES
This single institution retrospective study aims to evaluate the association between body mass index (BMI) and survival in glioblastoma (GBM).

METHODS
Patients were identified using a single institution cancer registry. Baseline height and weight were obtained at first clinical visit after diagnosis. Inclusion criteria were GBM diagnosis after 1999 with available height and weight data. Follow up was through July 2018.

RESULTS
779 patients were included who had available BMI data. Median age was 58 (IQR 48–66). 38% of patients were female and 62% were male. Median overall survival (OS) was 1.34 years (IQR 0.78–2.12) and median BMI was 26.01 (IQR 23.3–29.1). There was no strong linear correlation between OS and BMI using Pearson correlation (r=0.045). Patients with higher BMI had significantly improved OS when comparing the top 50% to bottom 50% (2.20 vs 1.89 years, p=0.03) and top 25% to bottom 25% (2.25 vs 1.84 years, p=0.03). When comparing patients classified as overweight or obese (BMI >/= 25) to those within normal range or below (BMI < 25), there was a trend towards increased OS (2.14 vs 1.90 years, p=0.075). There was no significant trend for BMI when comparing patients with higher OS with lower OS. There was also no significance for BMI on Cox proportional hazard multivariate analysis.

CONCLUSIONS
There was no significant linear correlation between BMI and survival for GBM patients, although there appears to be statistically significant improved survival benefit for patients with higher BMI compared to patients with lower BMI. Further investigation is warranted to explore this finding and if BMI could be used as a potential prognostic marker for GBM.
HOUT-08. PATIENT AND PHYSICIAN PERSPECTIVES ON LUMBAR PUNCTURE
Authors: Umemura Yoshie , Weill Benjamin , Khan Baber , Buthorn Justin , Ridder Andrew , Nevel Kathryn , Panageas Katherine , Boire Adrienne 
Published: November 2019

Abstract

OBJECTIVE
To investigate patients’ and physicians’ perceptions of lumbar puncture (LP) and tolerability.

METHODS
Adult patients were surveyed prior to and after the procedure regarding patient perceptions and actual experience of LP. Presence of symptoms pre- and post-LP were compared by McNemar test; symptom severity score was rated 0–10, compared by Wilcoxon test; and relative risks were compared by Fisher’s exact test. In addition to patient surveys, email requests to complete an eight-question survey regarding LP tolerability was sent to faculty physicians at two academic centers.

RESULTS
A total of 154 patients and 302 physicians completed the surveys during 1/2017-5/2019. Ninety-one patients (59%) reported anxiety prior to-LP compared to 52 (34%) who reported anxiety after the LP (p< 0.0001). Whereas 74% of patients predicted LP to be painful prior to LP, only 48% reported that LP was painful after the procedure (p< 0.0001). On an 11-point scale, patients anticipated significantly greater pain from LP than they reported after the procedure (mean 3.4 and 2.0 respectively, p< 0.0001). Patients who anticipated pain were more likely to experience pain (RR=1.65, 95% CI 1.07–2.73). There was no significant difference in symptoms such as headache, nausea, generalized pain, vision or gait disturbance before and after the procedure. After the LP, 117 patients (77%) answered they would repeat LP if recommended by their doctors. Out of 302 physicians (40% women), the majority (81%) felt that the LP induces anxiety or worry in patients, and 50% answered that the LP is painful for patients in general.

CONCLUSION
We observed that although anticipation of pain contributed to pre-procedure anxiety, LP was generally well-tolerated. The majority of patients experienced minimal pain. The results of this study suggest that measures to reduce pre-procedure anxiety may improve the tolerability of LP, an important diagnostic tool in neuro-oncology.