bluuebunny/crossref_metadata_2025_split huggingface dataset:
MNGI-12. PLEIOTROPIC MLLT10 VARIATION CONFERS RISK OF MENINGIOMA, BREAST, AND OVARIAN CANCERS
Authors: Walsh Kyle , Zhang Chenan , Calvocoressi Lisa , Hansen Helen , Berchuck Andrew , Schildkraut Joellen , Bondy Melissa , Wiemels Joseph , Claus Elizabeth 
Published: November 2019

Abstract

BACKGROUND
Women ages 35–44 have three-fold higher risk of meningioma compared to men. Epidemiologic studies have implicated exogenous hormone use, but endogenous hormonal factors are inconsistently associated. Elevated body mass index (BMI) is consistently associated with meningioma risk in both men and women, and personal history of breast cancer has also been associated with meningioma risk. Recent genome-wide association studies (GWAS) have identified a meningioma risk locus on chromosome 10p12 near previous GWAS hits for breast and ovarian cancers.

METHODS
To elucidate the pleiotropic role of 10p12 variation in predisposition to diverse tumors - possibly via a common mediating factor - we performed imputation‐based fine‐mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28108 cases, 22209 controls), and ovarian cancer (25509 cases, 40941 controls). Analyses were stratified by sex (meningioma), estrogen receptor status (breast), and histotype (ovarian), then combined using ASSET meta-analysis. Lead variants were queried for association with >700 additional traits to identify potential effect-mediators.

RESULTS
Two-sided ASSET meta-analysis identified a lead variant near the MLLT10 promoter (P=1.4x10-13) associated with significantly increased risk of meningioma in women (OR=1.42, 95% CI: 1.20–1.69) and non-significantly increased risk in men (OR=1.19, 95% CI: 0.91–1.57). The meningioma risk allele was also associated with ovarian cancer risk (OR=1.09, 95% CI: 1.06–1.12) and ER+ breast cancer risk (OR=1.05, 95% CI: 1.02–1.08), but protected against ER- breast cancer (OR=0.91, 95% CI: 0.86–0.96). The risk allele was associated with higher body fat percentage, waist circumference and BMI at genome-wide levels (P< 5.0x10-8), but mediation analysis adjusting for BMI did not attenuate its association with meningioma risk.

CONCLUSION
We identify a MLLT10 eQTL that confers risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, but which protects against ER- breast cancer. Our results implicate a possible estrogenic mechanism underlying meningioma tumorigenesis.
PATH-18. CSF-DERIVED CIRCULATING TUMOR DNA REFLECTS DISEASE COURSE AND CLONAL EVOLUTION IN MEDULLOBLASTOMA
Authors: Liu Anthony P Y , Kumar Rahul , Smith Kyle , Robinson Giles , Gajjar Amar , Northcott Paul 
Published: November 2019

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in young children. A multi-modal approach comprises standard of care, and recent advances in molecular studies have identified clinically relevant subgroups. Nonetheless, 30% of MB patients relapse or progress, conferring dismal prognosis. Such suboptimal outcome is partly due to a lack of sensitive biomarkers for response-adapted personalization of treatment and relapse prediction. Circulating tumor DNA has been shown to correlate with disease status in a variety of adult cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. Here, we aim to evaluate the utility of profiling cell-free DNA (cfDNA) derived from longitudinally-banked cerebrospinal fluid (CSF) samples collected from children with MB enrolled in two prospective, multi-center trials (SJMB03 and SJMB12, estimated sample size of 100 patients, including 50 with subsequent progression). cfDNA was extracted, quantified, and analyzed for size distribution from pre-centrifuged CSF serially banked during the course of treatment and follow-up. Low-pass whole genome sequencing (LP-WGS) enabled detection of chromosomal and focal copy number alterations (CNAs). CNAs detected in cfDNA were compared against known somatic changes in corresponding primary tumors. Detectability of tumor-specific CNAs in cfDNA was then correlated with tumor burden and patient outcome. Pilot analysis showed presence of arm level and/or focal CNAs in cfDNA from 80% of CSF samples in 20 children with metastatic MB, and longitudinal assessment revealed correlation with clinical course throughout treatment with radiotherapy and chemotherapy. Further comparison of tumor and longitudinal cfDNA derived CNAs revealed divergent genomic alterations implicating potential oncogenic mechanisms underlying treatment failure and recurrence. Our study performed on a large prospective series of MB trial patients substantiates the utility of CSF derived cfDNA as an actionable biomarker in high-risk MB patients while also facilitating understanding of tumor evolution and heterogeneity.
PATH-26. CHARACTERIZING GENETIC DIFFERENCE IN CYSTIC GLIOBLASTOMA
Authors: Chen Zhihua , Long Xidai , Miao Yifeng , Zhou Xuan , Rockne Russell 
Published: November 2019

Abstract
Glioblastoma (GBM) is characterized by widespread genetic and transcriptional heterogeneity. Cystic GBM (cGBM) as a rare type, yet the cause of cyst formation and their bioinformatics about the role of the epigenome in disease progression are still unknown. We believe that there are certain factors that cause the entity of tumor to dissolve, leading to the formation of cavities inside the tumor. Exploring the is mechanism and key gene targets may become important strategies for future treatment. Here, we present genome-scale maps of DNA methylation, WES and whole transcriptome sequence in matched cGBM and noncGBM, as well as MRI image digital analysis and immunology scales to investigate the difference between these two groups. Firstly, we find that they are totally two different groups by transcription start site (TSS) Upstream and downstream methylation distribution. When Cgbm VS NONCgbm, There are 220 sites are up-regulation and 6273 sites are down-regulation. Next, whole transcriptome Sequence result showed that 2934 differential mRNA are down-regulation and 4524 differential mRNA are up-regulation in cGBM group, compare with noncGBM. At the same time, 896 differential genes are down-regulation and 1044 differential genes are up-regulation in cGBM group; 1744 differential IncRNA are down and 1643 differential IncRNA are up. Finally, we didn’t find different novel gene on whole transcriptome sequence. This is the first time we detect the varieties between cGBM and noncGBM based on the realm of DNA methylation, WES and whole transcriptome sequence. The further analyses deserve to do to explain the formation of cyst in tumor and vital gene target, which could be benefit to new treatment decision.
PATH-42. IDH-MUTANT LOWER-GRADE ASTROCYTOMAS CAN BE STRATIFIED FOR RISK BY CDKN2A, CDK4 AND PDGFRA COPY NUMBER ALTERATIONS
Authors: Rui Yang Ryan , Ka-Wai Li Kay , Ng Ho-Keung 
Published: November 2019

Abstract
In the 2016 WHO classification of tumors of the CNS, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower-grade astrocytomas and IDH mutated astrocytomas is now regarded as a single group with good prognosis. However, the molecular and clinical heterogeneity among IDH-mutant lower-grade astrocytomas have only rarely been investigated. In this study, we recruited 161 IDH-mutant lower-grade astrocytomas, and examined PDGFRA amplification, CDKN2A deletion, and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing, and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A deletion, and CDK4 amplification in 18.6%, 14.9%, and 18.0% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (p< 0.0001) and OS (p< 0.0001). In tumors without PDGFRA amplification, CDKN2A deletion was associated with a shorter PFS (p=0.0332). Tumors were then divided into three risk groups based on the presence of molecular alterations: high-risk (PDGFRA amplification), intermediate-risk (CDKN2A deletion or CDK4 amplification) and low-risk (neither CDKN2A deletion, CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.2, 62.9, and 71.8 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (p=0.036) and low-risk (p< 0.0001) groups. Our data illustrate that IDH-mutant lower-grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.
PATH-47. TTF MAY APPLY SELECTIVE PRESSURE TO GLIOBLASTOMA CLONES WITH ANEUPLOIDY: A CASE REPORT
Authors: Ruff Michael , Clarke Nathan , Kizilbash Sani , Carabenciov Ivan , Uhm Joon , Jenkins Robert 
Published: November 2019

Abstract

BACKGROUND
The Tumor Treating Fields (TTF) mechanism of action is hypothesized act upon mitosis by disrupting the cell spindle apparatus. However, biomarkers and human tissue correlation of the effect of the TTF device are lacking. CASE: A 41 year-old previously healthy woman was found to have a right frontoparietal glioblastoma after she developed subacute onset of left hemiparesis and headache. The tumor was IDH wild type MGMT promoter unmethylated and TERT mutated. Chromosomal Microarray (CMA) was performed and demonstrated genome wide aneuploidy primarily characterized by hyperdiploidy. She underwent a gross total resection of the enhancing portion of the tumor and subsequent standard chemoradiotherapy (60 Gy IMRT with concomitant temozolomide) followed by initiation of the TTF device and adjuvant temozolomide. Six months after diagnosis, after 72 days of using the TTF device with 75% compliance and completion of the third cycle of temozolomide the patient had radiographic recurrence. She underwent a repeat resection. Pathology demonstrated recurrent tumor. Genetic analysis no longer demonstrated chromosomal losses or gains: the tumor was diploid.

DISCUSSION
This case may be a demonstration of effect of the TTF device applying a selective pressure to cells with multiple chromosomal gains and losses as the efficiency of mitosis in these cells may already be severely compromised. We are currently performing CMA on all patients with available tissue treated with the TTF device at our institution, with a planned retrospective analysis to explore this hypothesis further.

CONCLUSION
Repeat resection with detailed genetic analysis of GBM recurrence after therapies may help generate hypotheses regarding mechanisms of resistance, and in this case, mechanisms of action of the TTF.
PATH-52. ANAPLASTIC PILOMYXOID ASTROCYTOMA HARBORING BRAF FUSION, PTEN AND TERT MUTATIONS
Authors: Kissoon Trisha , Gururangan Sridharan , Kresak Jesse , Governale Lance 
Published: November 2019

Abstract
Pilomyxoid astrocytomas (PMA) are focal neoplasms that are often cured with total resection. We present a case of a progressive PMA with histologic and molecular features suggestive of malignant transformation. A 13-year old boy presented with headaches, diplopia, and seizures. He had previously been followed for 7 years by serial imaging for a cystic/solid enhancing mass in the right temporal lobe without biopsy that had remained stable up to 6 months prior to his current illness. MRI of brain demonstrated significant progression of the solid component with extension into the subependymal portions of the lateral ventricles, leptomeningeal spread in brain and spine, and hydrocephalus. Patient underwent a partial resection of tumor and VP shunt placement. Pathology demonstrated a prominent myxoid matrix with angiocentric arrangement of monomorphous bipolar cells. PHH3 and Ki-67 stains confirmed multiple mitoses and elevated proliferation rate. Next Generation sequencing of tumor confirmed the presence of a KIAA1549-BRAF duplication/fusion, CDKN2A deletion, along with PTEN and TERT promoter mutations without BRAF V600E or ATRX mutations. The histology and molecular features was suggestive of a pilomyxoid astrocytoma (PMA) with anaplastic transformation. Patient is currently receiving carboplatin + vincristine plus a MEK inhibitor (TrametinibTM, Novartis Corporation, Cambridge, MA) for tumor control. We believe that the tumor was initiated by the oncogenic BRAF fusion and the dramatic progression and spread of disease after a long period of stability was probably related to recent acquisition of additional deleterious mutations that have been previously reported in anaplastic pilocytic astrocytoma.
PATH-55. MUTATIONS OF H3.3 AND H3.1 IN A LARGE COHORT OF GLIOMAS
Authors: Sumrall Ashley , Mittal Sandeep , Phuphanich Surasak , Heimberger Amy , Eschbacher Jenny , Korn Michael , Gatalica Zoran , Pandey Manjari , Xiu Joanne 
Published: November 2019

Abstract
Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are difficult to treat. We surveyed a large cohort of gliomas for H3-mutations, including H3K27m. Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2019 were analyzed. NextGen sequencing was done on 592 genes; MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing. Of nearly 1800 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. H3 mutations were more prevalent in pediatric tumors, and all H3 mutations seen in pediatric tumors were from grade IV tumors. Among the H3-mutated adult tumors, histology differed. There were 2 grade II tumors, 1 low grade glioma, 1 anaplastic ganglioglioma, and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53, ATRX, NF1, PDGFRA, FGFR1, FBXW7, BLM, and TSC2 compared with H3-WT. The H3-WT tumors were more enriched for MGMT-methylation and PTEN mutation. In H3-mutated tumors that were MGMT-methylated, most H3-mutations seen were G34R while K27M was largely exclusive. There was a heterogeneous distribution of H3 mutations, and the co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we can develop insight into novel treatment strategies for a class of tumors with historically dismal prognosis.
PATH-58. REAPPRAISAL OF HISTOLOGICAL FEATURES AND MOLECULAR ANALYSIS OF LOWER GRADE GLIOMAS AND ASSOCIATION WITH OVERALL SURVIVALS
Authors: Pareira Eriel , Ohara Kentaro , Shibuya Makoto , Nakagawa Yu , Yoshida Kazunari , Sasaki Hikaru 
Published: November 2019

Abstract

INTRODUCTION
Based on WHO 2016 classification of grade II and III glioma (lower grade glioma/LrGG), the pathological diagnosis of oligodendroglioma is associated with IDH mutation status and 1p/19q codeletion. It was reported that the classical oligodendroglioma features closely related to the presence of 1p/19q codeletion. In this study, we compared histology of oligodendroglial features with molecular prognostic factors such as ATRX, TERT, IDH1/2 and copy number aberrations and their relations with patients’ prognoses.

METHODS
In this study, we analyzed 94 cases of primary LrGG resected in 1990 to 2016 in Keio University Hospital, Japan. Using WHO 2007 classification of LrGG, we re-diagnosed the tumors based on their histological features and compared them to their initial diagnoses (made by the pathologists on the time of resections). The presence of classic for oligodendroglioma (CFO) features were closely documented. ATRX mutation was analyzed by immunohistochemistry. IDH1/2 and TERT mutation status were analyzed using Sanger sequence. Copy number aberrations analyzed using comparative genomic hybridization (CGH). In addition, we analyzed IDH-mut/codeleted tumors with cancer genetic panel.

RESULTS
Re-diagnosis shown there is a shift of trend toward oligodendroglioma diagnoses from astrocytoma and a trend of change from grade II to grade III. IDH-mut/codel tumors shown no correlation between CFO and molecular prognostic factors nor CNAs but there was correlation between overall survival and molecular factors such as CIC (p= 0.046) and FUBP1(p= 0.03). IDH-mut/non-codel tumors shown no correlation between CFO and overall survival but ATRX and gain of 8q were found to be correlated with pathological diagnosis.

CONCLUSION
There is a lot of change in histological diagnosis of oligodendroglioma from each eras. IDH-mut/codel tumors shown there is correlation between FUBP1 and CIC with overall survivals. IDH-mut/noncodel tumors shown there is correlation between gain of 8q with overall survivals.
PATH-60. PRIMARY CNS LYMPHOMA PRECEDED BY ACUTE DEMYELINATION
Authors: Low Justin , Buckley Anne , Randazzo Dina 
Published: November 2019

Abstract
Primary CNS lymphoma commonly presents with nonspecific encephalopathy or focal neurologic deficits. Magnetic resonance imaging typically shows a homogeneously enhancing mass with surrounding edema. The imaging differential diagnosis is broad, and includes high grade glioma and neuroinflammatory conditions. Definitive diagnosis therefore requires biopsy. Here we present a case of primary CNS lymphoma that was diagnosed as an acute demyelinating process on initial biopsy. A 68 year old female presented with gait instability and vertigo. MRI showed right cerebellar and right trigonal enhancing lesions. Biopsy revealed an acute demyelinating inflammatory process and she was diagnosed with acute disseminated encephalomyelitis. She was treated with intravenous methylprednisolone followed by oral prednisone with resulting clinical and radiographic improvement. She was re-admitted to hospital 4 months later with encephalopathy. Imaging showed a new enhancing mass in the pericallosal frontal lobes. Repeat brain biopsy showed diffuse large B-cell lymphoma. This case illustrates a highly unusual situation of biopsy-proven central demyelination preceding a primary CNS lymphoma diagnosis. It raises a number of etiopathological questions concerning the coexistence and potential causal relationships between demyelination and lymphoma. Additionally, it highlights the need for repeat biopsy if clinical and radiographic suspicion for lymphoma persists despite an alternative initial biopsy result.
PATH-61. IMMUNOHISTOCHEMICAL PHENOTYPING AND SURVIVAL ANALYSIS OF WHO GRADE II-IV GLIOMAS
Authors: Poulos Nora , Sattiraju Srikar , Opalak Charles , Dozmorov Mikhail , Harrison Jason , Richard Hope , Broaddus William 
Published: November 2019

Abstract

INTRODUCTION
Specific genetic mutations are linked to clinical prognosis in gliomas. There has been increasing demand to understand the association between tissue biomarker expression and survival. Using patient-derived samples, WHO grade II-IV gliomas were evaluated by the protein-staining pattern of molecular markers of interest across tumor grade, and the association between their expression and survival was investigated.

METHODS
Tissue microarrays (TMA) containing duplicate 1 mm cores were generated from 78 gliomas (WHO grade II-IV) using an automated TMA system. Immunohistochemistry was performed per the manufactures recommendation to evaluate expression of: Wilms tumor 1 (WT1), platelet endothelial cell adhesion molecule (CD31), adhesion G protein-coupled receptor E5 (CD97), complement decay-accelerating factor (CD55), hypoxia inducible factor 1 subunit alpha (HIF1α), EGF-like module-containing mucin-like hormone receptor-like 3 (EMR3), integrin, and isocitrate dehydrogenase 1 (IDH1). Samples with moderate (+1) or intense (+2) staining to WT1, CD31, CD97, CD55, or HIF1α, or any staining to EMR3 or IDH1 mutation, were considered positive.

RESULTS
Of the 78 tumor samples, there were 11 (14%) WHO grade II, 22 (28%) grade III, and 45 (59%) grade IV gliomas. Across grade III gliomas, anaplastic astrocytomas had significantly higher positive WT1 (p=0.04), CD31 (p=0.002) and IDH1 wild-type (p< 0.0001) staining. High-grade (III & IV) gliomas had significantly higher positive staining for WT1 (p=0.013), CD31 (0.024), integrin (p=0.021), and IDH1 wild type (p=0.044). In all gliomas, positive staining for WT1 (p< 0.0001), CD31 (p=0.009), CD97 (p=0.024), EMR3 (p=0.036), and IDH1 wild type (p=0.0006) were associated with worse overall survival. After adjusting for patient age, positive staining for WT1 (p=0.003) was associated with worse overall survival.

CONCLUSION
Using immunohistochemistry, unique biomarker staining patterns were identified for WHO grade III anaplastic astrocytomas and for high-grade gliomas. Irrespective of grade, staining for WT1, CD97, CD31, EMR3, and IDH1 wild-type were associated with worse overall survival.
PATH-63. TRANSCRIPTIONAL SIGNATURES IN HISTOLOGIC STRUCTURES WITHIN GLIOBLASTOMA TUMORS MAY PREDICT PERSONALIZED TREATMENT SENSITIVITY AND SURVIVAL
Authors: Kersch Cymon , Claunch Cheryl , Ambady Prakash , Bucher Elmar , Schwartz Daniel , Barajas Ramon , Iliff Jeffrey , Heiser Laura , Muldoon Leslie , Neuwelt Edward 
Published: November 2019

Abstract

OBJECTIVE
Personalized treatment strategies in Glioblastoma multiforme (GBM) has been hampered by intra-tumoral heterogeneity. The goals of this study were to (1) determine the impact of intra-tumoral heterogeneity on established predictive and prognostic transcriptional signatures in human GBM, and (2) develop methods to mitigate the impact of tissue heterogeneity on transcriptomic-based patient stratification.

METHODS
We analyzed transcriptional profiles of GBM histological structures from the open-source Ivy Glioblastoma Atlas Project. To generate these data, infiltrative tumor, leading edge, cellular tumor [CT], perinecrotic zones, pseudopalisading cells, hyperplastic blood vessels and microvascular proliferation were microdissected from 34 newly diagnosed GBM and underwent RNA sequencing. Data from The Cancer Genome Atlas were used for validation. Principle component analysis, network analysis and gene set enrichment analysis were used to probe gene expression patterns.

RESULTS
Distinct biological networks were enriched in each tumor histological structure. Classification of patients into GBM molecular subtypes varied based on the structure assessed, with many patients classified as every subtype depending on the structure analyzed. Using only CT to classify subtypes, we identified biologically unique patterns suggesting that proneural and mesenchymal tumors may be more sensitive to chemoradiotherapy and immunotherapy, respectively. Survival outcome predicted by an established multigene panel was confounded by histologic structure. Utilizing CT transcriptomics we developed a novel survival prediction gene signature that identified the highest-risk GBM patients in both CT and bulk tissue gene expression profiles.

CONCLUSIONS
Histologic structures contribute to intra-tumoral heterogeneity in GBM. Using mixed-structure biopsy samples could incorrectly subtype tumors and produce invalid patient stratification. Limiting transcriptomic analysis to the CT allowed us to develop a new survival prediction gene signature that appears accurate even in mixed tissue samples. The biological patterns uncovered in the subtypes and risk-stratified groups have important implications for guiding the development of precision medicine in GBM.