bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBRS-04. MEDULLOBLASTOMA DETECTION BY BLOOD TEST
Authors: Yalon Michal , Toren Amos , Freedman Shany , Remke Marc , Meharian-Shai Ruty 
Published: December 2020

Abstract

INTRODUCTION
Long non coding RNAs (lincRNAs) are functionally defined as transcripts longer than 200 nucleotides in length with no protein coding potential. lincRNA involvement in human cancers etiology is being increasingly proved. Cancer-secreted long non-coding RNAs (lncRNAs) in exosomes are emerging mediators of cancer-host cross talk communication in tumor microenvironments. The ability to monitor and detect tumor markers in real time enables access to tumor biology and may allow highly personalized treatment for each patient. METHODS AND

RESULTS
We analyzed RNA sequencing of 64 Medulloblastoma samples and quantified the genome wide long non coding RNAs (lincRNA) expression levels. We identified a lincRNA that is distinctively highly expressed in group 4 (MB4). MB4 expression was further examined in microarray analysis on a larger cohort of medulloblastoma patient samples and a large cohort (n=1405) of patient samples that include normal brain and different brain tumor samples. MB4 proved to be specific and highly expressed in group 4 Medulloblastoma. MB4 was detected in the plasma of medulloblastoma patients with active disease, or subtotal resection. MB4 was not detected in patients that their tumors were resected. MB4 expression is not detected in the serum of medulloblastoma type SHH, penioblastoma, ewing sarcoma and neuroblastoma patients.

CONCLUSIONS
We have found that MB4 lncRNA is a highly specific medulloblastoma tumor biomarker and is sensitive and noninvasive biomarker that can be quantified from a blood test. MB4 can be a good diagnostic marker, and in future both may also be a good target for therapy.
MBRS-14. INTEGRATING CLINICAL AND GENOMIC CHARACTERISTICS IN PEDIATRIC MEDULLOBLASTOMA SUBTYPES IN A SINGLE COHORT IN TAIWAN
Authors: Wu Kuo-Sheng , Wong Tai-Tong 
Published: December 2020

Abstract

BACKGROUND
Medulloblastoma (MB) was classified to 4 molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4) with the demographic and clinical differences. In 2017, The heterogeneity within MB was proposed, and 12 subtypes with distinct molecular and clinical characteristics.

PATIENTS AND METHODS: PATIENTS AND METHODS
We retrieved 52 MBs in children to perform RNA-Seq and DNA methylation array. Subtype cluster analysis performed by similarity network fusion (SNF) method. With clinical results and molecular profiles, the characteristics including age, gender, histological variants, tumor location, metastasis status, survival, cytogenetic and genetic aberrations among MB subtypes were identified.

RESULTS
In this cohort series, 52 childhood MBs were classified into 11 subtypes by SNF cluster analysis. WNT tumors shown no metastasis and 100% survival rate. All WNT tumors located on midline in 4th ventricle. Monosomy 6 presented in WNT α, but not in β subtype. SHH α and β occurred in children, while SHH γ in infant. Among SHH tumors, α subtype showed the worst outcome. G3 γ showed the highest metastatic rate and worst survival associated with MYC amplification. G4 α has the highest metastatic rate, however G4 γ showed the worst survival.

CONCLUSION
We identified molecular subgroups and subtypes of MBs based on gene expression and DNA methylation profile in children in our cohort series. The results may contribute to the establishment of nation-wide correlated optimal diagnosis and treatment strategies for MBs in infant and children.
MBRS-23. SIGNIFICANCE OF mi-R33 IN GENERATION AND PROGRESSION OF MEDULLOBLASTOMA
Authors: Matsui Yasuzumi 
Published: December 2020

Abstract
Lipid metabolism has been shown to be associated with tumorigenicity in various malignancies. The purpose of this study was to investigate the association of miR-33, a key regulator of lipid metabolism, in tumorigenicity and progression of medulloblastoma. miR-33a is an only isotype of miR-33 in rodents although miR-33b is also detected in human. Incidence of medulloblastoma and histopathological findings were compared between ptch1+/- mice and ptch1+/- miR-33a-/- mice. Effect of miR-33b upregulation by cordycepin was tested in DAOY medulloblastoma cells both in vitro and in vivo. Knockout of miR-33a in ptch1+/- transgenic mouse model increased the incidence of spontaneous generation of medulloblastoma from 19.8% to 49.5% (p &lt; 0.001) at 10 months. Cordycepin, which upregulates miR-33b, prevented tumor growth in DAOY human medulloblastoma cell line, but the effect was not evident in an orthotopic mouse medulloblastoma model. Although miR-33 seems to be an important regulator of medulloblastoma, treatment efficacy of cordycepin was not enough. Combination treatment with immunotherapy or cytotoxic treatment needs to be tested to show survival benefit in preclinical models.
MBRS-38. MOLECULAR CLASSIFICATION AND CLINICAL CHARACTERISTICS OF 236 MEDULLOBLASTOMAS IN JAPAN
Authors: Kanemura Yonehiro , Shofuda Tomoko , Yoshioka Ema , Kanematsu Daisuke , Ichimura Koichi , Sasaki Atsushi , Inoue Takeshi , Hirato Junko , Kodama Yoshinori , Mano Masayuki , Shibui Soichiro , Arai Hajime , Sakamoto Hiroaki , Date Isao , Nishikawa Ryo 
Published: December 2020

Abstract
Recent intensive genomic and molecular biological analyses have made a consensus that medulloblastomas (MBs) are at least classified into four core subgroups, and the new 2016 WHO brain tumor classification has introduced the classification of MBs genetically defined in addition to classical histopathological diagnosis. To establish a nationwide network of a molecular diagnosis system for pediatric brain tumors, the JPMNG co-organized by the Japan Society for Neuro-Oncology and the Japanese Society for Pediatric Neurosurgery have started the clinical researches in 2012, and we have summarized results of molecular analysis of Japanese MBs. Total 236 primary MBs have been subclassified by gene expression profile using the NanoString nCounter system or DNA methylation array, and their single nucleotide mutations and copy number aberrations have been also examined. Mean follow up time was 68.9 months. Proportion of four core subgroups were WNT (16.9%), SHH (25.4%), Group 3 (17.4%) and Group 4 (40.3%), respectively. In cases of less than 3 years old, no WNT have been found and 63.2% cases were SHH. In cases between 3 to 17 years old, Group 4 is the most (47%), and these trends is almost consistent with published references. TP53 mutations were identified in 23.3% of SHH, and they were significantly poor prognosis. Metastatic or MYC gain Group 3 MBs were poor prognosis, while Group 4 MBs with loss of chromosome 11 or whole chromosomal aberration were good prognosis. These findings reveal molecular properties of Japanese MBs and will contribute to develop new therapeutic strategies.
MBRS-51. MUTATIONS IN BRPF1 FOUND IN SHH MEDULLOBLASTOMA PREVENT INTERACTION WITH TP53 AND LEADS TO RADIORESISTANCE IN VITRO
Authors: Vouri Mikaela , Mercier Audrey , da Silva Patricia Benites Goncalves , Okonechnikov Konstantin , Forget Antoine , Yu Hua , Chivet Anais , Kool Marcel , Pfister Stefan , Ayrault Olivier , Kawauchi Daisuke 
Published: December 2020

Abstract
Medulloblastoma (MB) is one of the most common pediatric tumors in children. Among them, SHH subgroups of MB (MBSHH) is characterized by constitutive activation of SHH pathway. Somatic mutations in BRPF1, a chromatin modifier, is found in more than 5% of MBSHH and accounts for almost 20% of adult MBSHH but its potential role in MBSHH pathophysiology is still unknown. In this study, we first examined the function of Brpf1 on pro-tumorigenic features of MBSHH and evaluated molecular pathways regulated by Brpf1 using Brpf1floxed::Atoh1-Cre conditional knockout mice, in which Brpf1 is conditionally deleted in cerebellar granule neuron progenitors (GNPs). While RNA-seq analysis on GNPs from Brpf1 WT and KO mice showed significant differences in the pathways related with cell cycle and cell death, deletion of Brpf1 did not cause acceleration of tumorigenesis in the Ptch1 heterozygous tumor-prone. Background: Co-immunoprecipitation followed by mass spectrometry analysis identified interaction partners of BRPF1 including MOZ, MORF and ING5, known partners of BRPF1. Gene ontology analysis also depicted pathways important for cell cycle progression, cell death and response to DNA damage. Consistent with these observations, TP53 was identified as a novel co-factor of BRPF1. Of note, some of MBSHH-relevant BRPF1 mutations prevented interaction with TP53. According to the previous finding that cytosolic TP53 is required for apoptotic cell death, GNPs expressing the BRPF1-R600X mutant gene exhibited the resistance to irradiation-induced cell death. In conclusion, our data revealed that BRPF1 mutants found in MBSHH could prevent the complex formation with TP53, leading to enhanced resistance to cell apoptosis.
MBRS-53. CONTROL OF MEDULLOBLASTOMA VASCULATURE BY A REGULATOR OF NEUROGENESIS
Authors: Shaik Shavali , Maegawa Shinji , Haltom Amanda , Dobson Tara , Schadler Keri , Gopalakrishnan Vidya 
Published: December 2020

Abstract
Medulloblastomas are characterized by poor neuronal lineage specification. Expression of the RE1 Silencing Transcription Factor (REST), a regulator of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Using a novel transgenic mouse (RESTTG) model, we demonstrated that REST is a driver of medulloblastoma genesis and promotes tumor progression in mice with loss of an allele of Ptch1 (Ptch+/−). Tumor formation in Ptch+/−/RESTTG mice occurred with 100% penetrance and a latency of 10–90 days in contrast to Ptch+/− mice, which developed tumors at a frequency of 15–20% at 6–9 months of age. Histopathological analyses showed leptomeningeal dissemination of tumors in Ptch+/−/RESTTG mice, in addition to a significant increase in tumor vasculature compared to tumors in Ptch+/− mice. These findings were recapitulated in xenografted tumors of isogenic low and high-REST medulloblastomas in mice. Proteome profiler human angiogenesis array analyses revealed a REST-dependent increase in vascular endothelial growth factor (VEGF) and placental growth factor (PLGF). Surprisingly, REST elevation also caused co-localization of tumor cells with tumor vasculature, specifically endothelial cells, and was associated with upregulated expression of a number of pro-angiogenic genes, including receptor VEGFR1 and the positive regulator of endothelial differentiation, E26 transformation specific-1 (ETS1), in tumor cells. In addition, expression of several anti-angiogenic molecules was downregulated. Knockdown of ETS1 reversed the above findings. Thus, our data demonstrate that REST elevation not only blocks neurogenesis in medulloblastoma cells, but also modulates the tumor microenvironment by mechanisms that likely involve vascular mimicry.
MBRS-54. POOR SURVIVAL IN REPLICATION REPAIR DEFICIENT HYPERMUTANT MEDULLOBLASTOMA AND CNS EMBRYONAL TUMORS: A REPORT FROM THE INTERNATIONAL RRD CONSORTIUM
Authors: Das Anirban , Bianchi Vanessa , Edwards Melissa , Varghese Nobish , Sudhaman Sumedha , Farah Roula , Dvir Rina , Reddy Alyssa , Raskin Salmo , Hansford Jordan , Hamid Syed Ahmer , Hsu Saunders , Yen Lee Yi , Quider Abed Abu , Ghalibafian Mithra , Koustenis Elisabeth , Al-Battashi Abeer , Mason Gary , Lee Joung , Bell Danille , Stearns Duncan , Ziegler David , Zapotocky Michal , Lasaletta Alvaro , Kulkarni Abhaya , Tsang Derek S , Laperriere Normand , Hawkins Cynthia , Bouffet Eric , Ramaswamy Vijay , Tabori Uri 
Published: December 2020

Abstract

BACKGROUND
Mutations in mismatch repair (MMR) and DNA-polymerase (POL) genes lead to DNA replication repair deficiency (RRD), resulting in a growing group of previously under-recognized childhood brain tumors. Medulloblastoma and embryonal tumors are rarely reported in RRD. Their biological and clinical significance is unknown.

METHODS
We analyzed the clinical and genomic data of embryonal tumors registered in the International RRD Consortium.

RESULTS
Twenty-six tumors were centrally reviewed to confirm medulloblastoma (n=18), embryonal-tumor, NOS (n=5), and three glioblastoma (excluded). Embryonal tumors were observed at a young age (median: 7-years, IQR: 5;11), and all but one exhibited clinical cues (café-au-lait macules/ family history) of germline RRD. Medulloblastomas with RRD exhibited high-risk features, including anaplastic histology (50%), and SHH-subgroup with TP53-mutation (50%). Importantly, 68% harbored POLE/POLD1 mutations, resulting in median tumor mutation burden of 164 mut/mb. POL-mutated tumors were significantly ultra-hypermutated (&gt;100 mut/mb) than tumors with MMR-deficiency alone (p=0.015). Synchronous and metachronous tumors were observed in 40%. However 90% of the deaths were related to the diagnosis of embryonal CNS tumor. Median survival for the entire cohort was 17-months (95% CI: 10 to 23). Predicted 3-year survival was 37% for medulloblastoma, with no survivors among other embryonal tumors.

CONCLUSIONS
This is the largest cohort of replication repair deficient medulloblastoma reported till date. The tumors are hypermutated, harbor somatic mutations in TP53 and/or POLE/POLD1, and have very poor survival with current chemo-irradiation based approaches. These biologically unique tumors expand the spectrum of high-risk TP53-mutant SHH-medulloblastoma, and need novel strategies for treatment.
MBRS-56. RE-EVALUATION OF LEPTOMENINGEAL METASTASIS IN MEDULLOBLASTOMA WITH MAGNETIC RESONANCE IMAGING, RELATED SYMPTOMS AND CEREBROSPINAL FLUID METABOLOMIC PROFILES
Authors: Im Ji Hye , Yoo Byong Chul , Lee Jun Hwa , Kim Kyung-Hee , Kim Jong Heon , Park Hyeon Jin , Park Meerim , Kwon Ji Woong , Shin Sang Hoon , Yoo Heon , Choi Seung Ah , Yang Jae Yeol , Phi Ji Hoon , Kim Seung-Ki , Gwak Ho-Shin 
Published: December 2020

Abstract

BACKGROUND
Diagnosis of leptomeningeal metastasis (LM) in medulloblastoma is made by positive findings in either MRI or CSF cytology. We studied if CSF metabolomics profile can differentiate the discordant results between MRI and CSF cytology and reflect the sampling time related to treatment.

MATERIALS AND METHODS
We prospectively collected 83 CSF samples from 45 medulloblastoma patients. A total of 6,527 low-mass ions (LMIs) were detected using liquid chromatography tandem mass spectrometry (LC-MS/MS). Discriminative low-mass ions (LMIs) between four different MRI and cytology results groups were evaluated and representative LMIs were identified.

RESULTS
CSF cytology and MRI finding were both positive for LM in 8 samples and both negative for 47 samples. Tests were cytology (-) and MRI (+) in 20 samples, whereas cytology (+) and MRI (-) status were in the remaining 8 samples. The diagnostic accuracy by area under the curve (AUC) was 0.722 for cytology and 0.888 for MRI each. Based on the exclusiveness of LMI between groups, we verified 27 discriminative LMIs in MRI (+)/ cytology (+), 9 LMIs in MRI (+)/ cytology (-), and 12 LMIs in MRI (-) and cytology (+) group, separately. Metabolic pathways involved in MRI (+)/ cytology (+) group were linoleic acid, phenylalanine, TCA cycle, retinol, arginine-ornithine, nicotinate-nicotinamide, etc. Low-mass-ion discriminant equation (LOME), which could differentiate both different MRI and cytology results and the sampling time or presence of LM-related symptoms was found.

CONCLUSION
Non-targeted MSanalysis CSF metabolite in medulloblastomas revealed significantly different profiles, and these results suggest LMI profiles might have a higher sensitivity for LM diagnosis than either MRI or cytology.
MBRS-64. STUDY OF ARGININE METHYL TRANSFERASES IN MEDULLOBLASTOMA
Authors: Cheng Donghang , Taylor Pete , Gireud Monica , Maegawa Shinji , Yang Yanwen , Majumder Sadhan , Gopalakrishnan Vidya 
Published: December 2020

Abstract
Medulloblastoma is the most common malignant pediatric cancer and a leading cause of childhood cancer-related mortality. There is dire need for new therapies. Molecular sub-classification of medulloblastomas has identified chromatin modifiers as potential drivers of tumorigenesis. Expression of the RE1 Silencing Transcription Factor (REST), a hub for assembly of repressive chromatin remodelers and a known regulator of neurogenesis, is elevated in a subset of human sonic hedgehog (SHH) subgroup medulloblastomas, and is associated with poor prognosis. Using a novel transgenic mouse model, we showed REST to be a driver of medulloblastoma development. Surprisingly, our studies also revealed a role for REST in promoting proliferation of granule cell progenitors (GCPs), the cells of origin of SHH-driven medulloblastoma, and a concomitant loss of telomeres and increased genomic instability. We performed a gain of function screen using a library of chromatin modifiers to understand the mechanism by which proliferative potential was maintained, despite the loss of telomeres. This screen identified the Protein Arginine Methyltransferase 6 (PRMT6) as a high confidence hit. PRMT6 upregulation caused a reduction in CDKN2A, an important regulator of replicative senescence. Evasion of senescence is frequently implicated in tumor progression. Using a chemical screen, we also identified a novel, selective, reversible and competitive inhibitor of PRMT6. The consequence of genetic and pharmacological inhibition of PRMT6 on cell proliferation and senescence will be reported. Thus, our studies are the first to demonstrate a role for arginine methyl transferase family of chromatin modifiers in medulloblastoma genesis.
MBRS-69. METABOLITE PROFILING OF SHH MEDULLOBLASTOMA IDENTIFIES A SUBSET OF CHILDHOOD TUMOURS ENRICHED FOR HIGH-RISK MOLECULAR BIOMARKERS AND CLINICAL FEATURES
Authors: Bennett Christopher , Kohe Sarah , Burte Florence , Rose Heather , Hicks Debbie , Schwalbe Ed , Crosier Stephen , Storer Lisa , Lourdusamy Anbarasu , Wilson Martin , Avula Shivaram , Mitra Dipayan , Dineen Robert , Bailey Simon , Williamson Daniel , Grundy Richard , Clifford Steven , Peet Andrew 
Published: December 2020

Abstract
SHH medulloblastoma patients have a variable prognosis. Infants (&lt;3–5 years at diagnosis) are associated with a good prognosis, while disease-course in childhood is associated with specific prognostic biomarkers (MYCN amplification, TP53 mutation, LCA histology; all high-risk). There is an unmet need to identify prognostic subgroups of SHH tumours rapidly in the clinical setting, to aid in real-time risk stratification and disease management. Metabolite profiling is a powerful technique for characterising tumours. High resolution magic angle spinning NMR spectroscopy (HR-MAS) can be performed on frozen tissue samples and provides high quality metabolite information. We therefore assessed whether metabolite profiles could identify subsets of SHH tumours with prognostic potential. Metabolite concentrations of 22 SHH tumours were acquired by HR-MAS and analysed using unsupervised hierarchical clustering. Methylation profiling assigned the infant and childhood SHH subtypes, and clinical and molecular features were compared between clusters. Two clusters were observed. A significantly higher concentration of lipids was observed in Cluster 1 (t-test, p=0.012). Cluster 1 consisted entirely of childhood-SHH whilst Cluster 2 included both childhood-SHH and infant-SHH subtypes. Cluster 1 was enriched for high-risk markers - LCA histology (3/7 v. 0/5), MYCN amplification (2/7 v. 0/5), TP53 mutations (3/7 v. 1/5) and metastatic disease - whilst having a lower proportion of TERT mutations (0/7 v. 2/5) than Cluster 2. These pilot results suggest that (i) it is possible to identify childhood-SHH patients linked to high-risk clinical and molecular biomarkers using metabolite profiles and (ii) these may be detected non-invasively in vivo using magnetic-resonance spectroscopy.
MODL-08. OPTIMIZATION OF A NOVEL LOCAL DELIVERY SYSTEM FOR THE TREATMENTS OF SUPRATENTORIAL EPENDYMOMA
Authors: Ruff Lisa , Parkins Chris , Terranova Sabrina , Nathan Erica , Kasapidou Paraskevi , Lang Renata , Scherman Oren , Gilbertson Richard J 
Published: December 2020

Abstract
Ependymomas are the third most common paediatric brain tumour, incurable in up to 40% of cases. Until recently, ependymomas were regarded as a single disease group with all patients receiving combinations of maximal surgical resection and radiotherapy. Use of chemotherapy has been limited by the resistant nature of the tumour and poor access to tumours behind the blood brain barrier (BBB). It is now known that ependymoma comprises up to nine different molecular subgroups. One subgroup is characterized by a novel fusion protein, C11orf95-RELA, which acts as a potent driver of oncogenesis resulting in a poor prognosis. Here, we present the optimization of a novel drug delivery system that uses biodegradable hydrogels to deliver drugs with potent anti-ependymoma properties into post-resection cavity of supratentorial ependymoma. Our previous high-throughput in-vivo drug screens identified candidate ependymoma therapies with poor BBB penetrance properties. Using in-vitro delivery assays, we have confirmed and monitored the release of these compounds from the hydrogel. Additionally, we have implemented this delivery system in our preclinical mouse hospital in which mice receive standard-of-care surgery and radiotherapy. The efficacy of hydrogel-based delivery of these compounds is now being tested preclinically, in combination with radiotherapy. Treatment for ependymoma patients have not changed in the last 30 years and therefore an effective chemotherapy could add a great survival benefit to in the clinic.
MODL-13. GENETICALLY ENGINEERED PIG MODEL OF RHABDOID TUMOR PREDISPOSITION SYNDROME-1
Authors: Na Brian , Rubinstein C Dustin , Meudt Jennifer J , Biegel Jaclyn A , Judkins Alexander R , Lehman Brent P , Reichert Jamie L , Vitte Jeremie , Shanmuganayagam Dhanansayan , Giovannini Marco 
Published: December 2020

Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RT demonstrate genomic alterations in the SMARCB1 gene. There are two major hurdles in the development of safe and effective treatments for AT/RT: first, the mouse models do not fully recapitulate the disease seen in patients and their predictivity of clinical efficacy is still unproven. Second, due to a small patient population, the ability to recruit enough patients for clinical trials is challenging. Genetic studies have demonstrated that germline deletion of SMARCB1 exons 4 and 5 predisposes to AT/RT at an early age. Comparison of human, swine, and mouse SMARCB1 genes show similarities in gene and protein structure, with 100% amino acid identity between swine and human SMARCB1 isoforms. Thus, we hypothesized that germline deletion of exons 4 and 5 will predispose heterozygote swine to AT/RT development. SMARCB1+/- founder pigs are obtained using a CRISPR/Cas9 mediated gene-editing of conventional crossbred swine embryos, followed by embryo transfer into female swine surrogates. They are evaluated for clinical criteria used to diagnose AT/RT and by MRI at 6, 12, and 24 months of age, followed by histopathology and molecular analysis of the tumors as they are detected. Generating a large animal model of AT/RT would represent a breakthrough in the field from a genomic, pathophysiologic, pre-clinical and therapeutic perspective.