DOCSLIB.ORG

Impact of RNA-Sequencing Analysis in Refining Diagnosis in Pediatric Neuro-Oncology Kathleen M

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Impact of RNA-Sequencing Analysis in Refining Diagnosis in Pediatric Neuro-Oncology Kathleen M Impact of RNA-sequencing analysis in refining diagnosis in pediatric neuro-oncology Kathleen M. Schieffer1, Katherine E. Miller1, Stephanie LaHaye1, James Fitch1, Kyle Voytovich1, Daniel C. Koboldt1, Benjamin Kelly1, Patrick Brennan1, Anthony Miller1, Elizabeth Varga1, Kristen Leraas1, Vibhuti Agarwal2, Diana Osorio2, Mohamed S. AbdelBaki2, Jonathan L. Finlay2, Jeffrey R. Leonard3, Alex Feldman4, Daniel R. Boue4, Julie M. Gastier-Foster1, Vincent Magrini1, Peter White1, Catherine E. Cottrell1, Elaine R. Mardis1, Richard K. Wilson1 1. Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH; 2. Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH; 3. Department of Neurosurgery, Nationwide Children’s Hospital, Columbus, OH; 4. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH Background and demographics Methods Case 2: Refine diagnosis The Nationwide Children’s Hospital Institute for Genomic Medicine (IGM) translational research protocol Transcriptomic analysis was performed from 70 tissue sections collected from 56 patients: snap frozen (n=48), A 10-month-old was diagnosed with a sella/suprasellar tumor, most consistent with a CNS embryonal tumor. No enrolls pediatric patients with high-risk, relapsed, refractory, or difficult to classify tumors. The goal of formalin-fixed paraffin-embedded (FFPE) tissue (n=21), or disassociated cells (n=1). When possible, total RNA- constitutional or somatic variations or copy number aberrations were noted. The tissue was also sent to an this protocol is to refine the patient diagnosis, identify targeted therapeutics relevant to the individual sequencing was performed (n=60); however, when the sample was poor quality or low input, cDNA capture was outside institution for the Infinium MethylationEPIC 850K array, reporting a classification of pineoblastoma group tumor biology and eliminate unsuitable treatments, and determine eligibility for clinical trials. Findings utilized to enrich for exonic regions (n=8). RNA was unavailable for 2 patients. We aimed for a total of ≥80 million A/intracranial retinoblastoma (score=0.99). are reported and new cases identified for enrollment at weekly multidisciplinary tumor boards, mapped reads per sample, with 4 samples falling below that threshold (average mapped reads: 197,334,031 represented by oncology, surgery, pathology, radiology, radiation oncology, and IGM researchers. 148,456,775 reads). The analysis pipeline is described in Figure 3. A B Exon 1 2 3 4 5 6 7 8 9 - 11 12 13 14-17 18 19 20 21 22-23 24 25-27 Medically actionable findings are CLIA validated to allow for return of results to the medical record. To date, 56 unique pediatric patients with central nervous system (CNS) tumors have undergone comprehensive DNA-sequencing RNA-sequencing and gene-level expression Quantification Exon 1 2 3 4 5 6 7 8 9 - 11 12 13 14-17 18 19 20 21 22-23 24 25-27 genomic and transcriptomic analysis (Figure 1A). A majority of sequenced patients are male (60%) and between Constitutional and somatic Salmon tximport package variation RNA-sequencing Transcript-level the ages of 1-5 and 11-17 years-old (Figure 1B). Multiple tissue sections or time points were sequenced from Gene-level expression Assess for nonsense-mediated Tumor tissue(s) expression some patients, thus a total of 70 unique tissues were evaluated, with 66% of tissues from the primary tumor quantification decay and aberrant splicing quantification (Figure 1C). Constitutional and somatic Outlier analysis (protein-coding genes only) variation Identify reference cohort D A Yolk sac tumor (1) Single nucleotide variation, Differential C UCSC Treehouse cohorts Outlier metric Outlier criteria indels, copy number expression Germinoma (1) 1. Nervous system (n=434) Mahalanobis |Log2 fold change| Astrocytoma (3) variation/loss of heterozygosity, Quantile normalize Atypical teratoid rhabdoid tumor (1) 2. Non-nervous system distance and chi- >3.5 structural variation and calculate log2 Diffuse glioma (1) (n=194) squared P-value P <0.005 CNS neuroblastoma (1) fold change Ectopic retinoblastoma (1) Diffuse midline glioma (1) 3. Hematologic (n=479) ETMR (1) 3% Glioblastoma multiforme (4) Medulloblastoma (7) 20% Gliomatosis cerebri (1) Assess biological relevance 20% Oligodendroglioma (1) Clinical validation of medically actionable targets Therapeutic Pathway analysis Functional Clustering patterns Tumor cellularity targets Ingenuity Pathway Annotation Principal component Pineoblastoma (3) ESTIMATE 5% n=56 DGIdb Analysis DAVID analysis Atypical mixed glioneuronal tumor (1) 18% Pilocytic astrocytoma (8) Literature review to evaluate potential therapeutic targets CNS glioneuronal tumor (1) 16% Pleomorphic xanthoastrocytoma (2) Figure 3: IGM translational cancer protocol comprehensive DNA/RNA sequencing analysis pipeline. RNA-sequencing is performed on tumors to aid in DNET (2) 7% Ganglioglioma (3) 11% refining the patient diagnosis, identifying therapeutic targets, and confirming the transcriptional effects of constitutional and somatic DNA variation. High-grade neuroepithelial tumor (1) Rosette-forming glioneuronal tumor (1) Ependymoma (4) Choroid plexus carcinoma (5) Case 1: Refine diagnosis Choroid plexus papilloma (1) A 12-year-old was diagnosed with medulloblastoma, suggestive of Group 3 or Group 4, due to presence of B C isochromosome 17q. The patient recurred 3 years later. Six years after the initial diagnosis, the patient presented 25 3% 3% 3% Primary with a cerebellar lesion “most consistent with recurrent medulloblastoma”, with comment recommending genomic studies to confirm the morphologic impression. Figure 5: Refinement of a retinoblastoma diagnosis in the absence of constitutional RB1 variation. (A) RB1-SIAH3 fusion with fusion breakpoints at 20 exon 17 of RB1 and exon 2 of SIAH3. (B) Sashimi plot demonstrating a drastic reduction in spliced read depth following the fusion breakpoint at exon 17 of RB1 in the Recurrent described retinoblastoma case and consistent spliced read depth in a pineoblastoma patient with wild-type RB1. (C) Unsupervised three-dimensional principal component A +6 years Molecular refinement of analysis of the top 500 most variable protein-coding genes. (D) Unsupervised hierarchical clustering of the St. Jude-Pediatric Cancer Genome Project retinoblastoma cases 15 diagnosis (n=19) and our described case using 79 retina-associated genes. Metastatic +3 years Secondary diagnosis Female 25% Primary diagnosis Recurrence “most consistent with recurrent Secondary glioblastoma count 10 Male Medulloblastoma Medulloblastoma medulloblastoma” +6 years, 9 months 66% Residual Patient deceased Case 3: Identify targeted therapy 5 Second Gross total resection Resection Resection A 1-year-old with choroid plexus carcinoma was treated with gross total resection and chemoradiation. Genomic 0 malignancy Radiation + adjuvant chemotherapy Proton radiation + salvage chemotherapy Clinical trial + everolimus <1 y 1-5 y 6-10 y 11-17 y ≥18 y IGM seQuencing of primary and analysis identified a somatic TP53 mutation and 17p loss of heterozygosity. Comprehensive transcriptomic secondary tumors analysis revealed overexpression of multiple pathways (mTOR, FGF, and PDGF signaling) consistent with other Figure 1: Demographics of the IGM translational research protocol CNS cohort. (A) Primary diagnoses from 56 unique pediatric patients with CNS B Primary Secondary IGM choroid plexus carcinoma cases and a 2017 case report (Cornelius et al. 2017 Front. Pharmacol.). tumors who underwent comprehensive genomic and transcriptomic sequencing on our IGM translational cancer protocol. Patient diagnosis is segregated by WHO Treatment on sunitinib (PDGF inhibitor), everolimus (mTOR inhibitor), and thalidomide (FGF inhibitor) was classification of CNS tumors. ETMR: embryonal tumor with multilayered rosettes; DNET: dysembryoplastic neuroepithelial tumor. (B) Age and sex at primary tumor C diagnosis. (C) Distribution of tumor occurrence for the sequenced tissue sections. initiated. Hematoxylin A B Cohort findings and eosin A B Synaptophysin C Li-Fraumeni syndrome 8.9% 5 D 7.1% 4 Neurofibromatosis 3.6% 3 Klippel-Feil syndrome with 3.6% 3.6% 1.8% count nemaline myopathy 2 1.8% 1.8% 1.8% 1.8% Olig2 1 Nemaline myopathy 1.8% 0 F 1.8% Noonan syndrome D E QKI-RAF1 ST7-MET RB1-SIAH3 0 1 2 3 4 5 6 EP300-BCOR E 0.45 FGFR1-TACC1 F count C11orf95-RELA KIAA1549-BRAF 0.40 0.35 C 5% D 5% 0.30 5% FGF 0.25 ExampleExample EGF Refinement of diagnosis (5.4%) Overlap 26% 0.20 CaseCase 11 PDGF ”most consistent with medulloblastoma” à secondary 0.15 11% Secondary tumor VAF MET glioblastoma 0.10 NTRK CNS embryonal tumor à retinoblastoma 11% DNMT3B Low-grade neuroepithelial tumor à rosette-forming 0.05 n=17 (30.3%) 21% PI3K glioneuronal tumor 0.00 16% KIT 0.00 0.20 0.40 0.60 0.80 Primary tumor VAF Figure 6: Transcriptomic analysis identifies therapeutically-relevant targets in a pediatric choroid plexus carcinoma patient. (A) Manhattan plot visualizing genome-wide differential expression relative to the UCSC Treehouse nervous system cohort (n=434). Outliers are shown as a blue dot. Outliers that are targetable, as determined by DGIdb, are shown as a red dot. (B) Distribution of DESeq2 normalized counts for FGFR2 within the IGM translational research protocol Figure 4: Comprehensive sequencing of primary and secondary tumors refined diagnosis from medulloblastoma to secondary glioblastoma. cohort. (C) Same as (B) but for MTOR. (D) Boxplots showing the distribution of log2(TPM+1)
Load more

Recommended publications
  • Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies
    International Journal of Molecular Sciences Review Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies Maria Peleli 1,2,3,*, Aristidis Moustakas 1 and Andreas Papapetropoulos 2,3 1 Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden; [email protected] 2 Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece; [email protected] 3 Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece * Correspondence: [email protected]; Tel.: +46-768-795-270 Received: 28 August 2020; Accepted: 3 October 2020; Published: 6 October 2020 Abstract: Glioblastoma and other brain or CNS malignancies (like neuroblastoma and medulloblastoma) are difficult to treat and are characterized by excessive vascularization that favors further tumor growth. Since the mean overall survival of these types of diseases is low, the finding of new therapeutic approaches is imperative. In this review, we discuss the importance of the interaction between the endothelium and the tumor cells in brain and CNS malignancies. The different mechanisms of formation of new vessels that supply the tumor with nutrients are discussed. We also describe how the tumor cells (TC) alter the endothelial cell (EC) physiology in a way that favors tumorigenesis. In particular, mechanisms of EC–TC interaction are described such as (a) communication using secreted growth factors (i.e., VEGF, TGF-β), (b) intercellular communication through gap junctions (i.e., Cx43), and (c) indirect interaction via intermediate cell types (pericytes, astrocytes, neurons, and immune cells).
    [Show full text]
  • Leptomeningeal Dissemination of Pilocytic Astrocytoma Via Hematoma in a Child
    Neurosurg Focus 13 (1):Clinical Pearl 2, 2002, Click here to return to Table of Contents Leptomeningeal dissemination of pilocytic astrocytoma via hematoma in a child Case report MASARU KANDA, M.D., HIDENOBU TANAKA, M.D., PH.D., SOJI SHINODA, M.D., PH.D., AND TOSHIO MASUZAWA, M.D., PH.D. Department of Surgical Neurology, Jichi Medical School, Tochigi, Japan A case of recurrent pilocytic astrocytoma with leptomeningeal dissemination (LMD) is described. A cerebellar tumor was diagnosed in a 3-year-old boy, in whom resection was performed. When the boy was 6 years of age, recur- rence was treated with surgery and local radiotherapy. At age 13 years, scoliosis was present, but the patient was asymptomatic. Twelve years after initial surgery LMD was demonstrated in the lumbar spinal region without recur- rence of the original tumor. This tumor also was subtotally removed. During the procedure, a hematoma was observed adjacent to the tumor, but the border was clear. Histological examination of the spinal cord tumor showed features sim- ilar to those of the original tumor. There were no tumor cells in the hematoma. The MIB-1 labeling index indicated no malignant change compared with the previous samples. Radiotherapy was performed after the surgery. The importance of early diagnosis and management of scoliosis is emphasized, and the peculiar pattern of dissemination of the pilo- cytic astrocytoma and its treatment are reviewed. KEY WORDS • pilocytic astrocytoma • leptomeningeal dissemination • MIB-1 labeling index • radiation therapy • scoliosis
    [Show full text]
  • Central Nervous System
    PRINCESS MARGARET CANCER CENTRE CLINICAL PRACTICE GUIDELINES CENTRAL NERVOUS SYSTEM LOW GRADE GLIOMAS CNS Site Group – Low Grade Gliomas Author: Dr. Norm Laperriere 1. INTRODUCTION 3 2. PREVENTION 3 3. SCREENING AND EARLY DETECTION 3 4. DIAGNOSIS AND PATHOLOGY 3 5. MANAGEMENT 4 5.1 MANAGEMENT ALGORITHMS 4 5.2 SURGERY 4 5.3 CHEMOTHERAPY 5 5.4 RADIATION THERAPY 5 6. ONCOLOGY NURSING PRACTICE 6 7. SUPPORTIVE CARE 6 7.1 PATIENT EDUCATION 6 7.2 PSYCHOSOCIAL CARE 6 7.3 SYMPTOM MANAGEMENT 6 7.4 CLINICAL NUTRITION 7 7.5 PALLIATIVE CARE 7 7.6 REHABILITATION 7 8. FOLLOW-UP CARE 7 Last Revision Date – April 2019 2 Low Grade Gliomas 1. Introduction • Grade I gliomas: pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNET), pleomorphic xanthoastrocytoma, (PXA), ganglioglioma • Grade II gliomas: infiltrating astrocytoma, oligodendroglioma, mixed gliomas • annual incidence is approx. 1/100,000 This document is intended for use by members of the Central Nervous System site group of the Princess Margaret Hospital/University Health Network. The guidelines in this document are meant as a guide only, and are not meant to be prescriptive. There exists a multitude of individual factors, prognostic factors and peculiarities in any individual case, and for that reason the ultimate decision as to the management of any individual patient is at the discretion of the staff physician in charge of that particular patient’s care. 2. Prevention • genetic counseling for all NF1 carriers 3. Screening and Early Detection • baseline MRI brain for all newly
    [Show full text]
  • Charts Chart 1: Benign and Borderline Intracranial and CNS Tumors Chart
    Charts Chart 1: Benign and Borderline Intracranial and CNS Tumors Chart Glial Tumor Neuronal and Neuronal‐ Ependymomas glial Neoplasms Subependymoma Subependymal Giant (9383/1) Cell Astrocytoma(9384/1) Myyppxopapillar y Desmoplastic Infantile Ependymoma Astrocytoma (9412/1) (9394/1) Chart 1: Benign and Borderline Intracranial and CNS Tumors Chart Glial Tumor Neuronal and Neuronal‐ Ependymomas glial Neoplasms Subependymoma Subependymal Giant (9383/1) Cell Astrocytoma(9384/1) Myyppxopapillar y Desmoplastic Infantile Ependymoma Astrocytoma (9412/1) (9394/1) Use this chart to code histology. The tree is arranged Chart Instructions: Neuroepithelial in descending order. Each branch is a histology group, starting at the top (9503) with the least specific terms and descending into more specific terms. Ependymal Embryonal Pineal Choro id plexus Neuronal and mixed Neuroblastic Glial Oligodendroglial tumors tumors tumors tumors neuronal-glial tumors tumors tumors tumors Pineoblastoma Ependymoma, Choroid plexus Olfactory neuroblastoma Oligodendroglioma NOS (9391) (9362) carcinoma Ganglioglioma, anaplastic (9522) NOS (9450) Oligodendroglioma (9390) (9505 Olfactory neurocytoma Ganglioglioma, malignant (()9521) anaplastic (()9451) Anasplastic ependymoma (9505) Olfactory neuroepithlioma Oligodendroblastoma (9392) (9523) (9460) Papillary ependymoma (9393) Glioma, NOS (9380) Supratentorial primitive Atypical EdEpendymo bltblastoma MdllMedulloep ithliithelioma Medulloblastoma neuroectodermal tumor tetratoid/rhabdoid (9392) (9501) (9470) (PNET) (9473) tumor
    [Show full text]
  • Central Nervous System Tumors General ~1% of Tumors in Adults, but ~25% of Malignancies in Children (Only 2Nd to Leukemia)
    Last updated: 3/4/2021 Prepared by Kurt Schaberg Central Nervous System Tumors General ~1% of tumors in adults, but ~25% of malignancies in children (only 2nd to leukemia). Significant increase in incidence in primary brain tumors in elderly. Metastases to the brain far outnumber primary CNS tumors→ multiple cerebral tumors. One can develop a very good DDX by just location, age, and imaging. Differential Diagnosis by clinical information: Location Pediatric/Young Adult Older Adult Cerebral/ Ganglioglioma, DNET, PXA, Glioblastoma Multiforme (GBM) Supratentorial Ependymoma, AT/RT Infiltrating Astrocytoma (grades II-III), CNS Embryonal Neoplasms Oligodendroglioma, Metastases, Lymphoma, Infection Cerebellar/ PA, Medulloblastoma, Ependymoma, Metastases, Hemangioblastoma, Infratentorial/ Choroid plexus papilloma, AT/RT Choroid plexus papilloma, Subependymoma Fourth ventricle Brainstem PA, DMG Astrocytoma, Glioblastoma, DMG, Metastases Spinal cord Ependymoma, PA, DMG, MPE, Drop Ependymoma, Astrocytoma, DMG, MPE (filum), (intramedullary) metastases Paraganglioma (filum), Spinal cord Meningioma, Schwannoma, Schwannoma, Meningioma, (extramedullary) Metastases, Melanocytoma/melanoma Melanocytoma/melanoma, MPNST Spinal cord Bone tumor, Meningioma, Abscess, Herniated disk, Lymphoma, Abscess, (extradural) Vascular malformation, Metastases, Extra-axial/Dural/ Leukemia/lymphoma, Ewing Sarcoma, Meningioma, SFT, Metastases, Lymphoma, Leptomeningeal Rhabdomyosarcoma, Disseminated medulloblastoma, DLGNT, Sellar/infundibular Pituitary adenoma, Pituitary adenoma,
    [Show full text]
  • Differentiation Between Pilocytic Astrocytoma and Glioblastoma: a Decision Tree Model Using Contrast-Enhanced Magnetic Resonance
    European Radiology (2019) 29:3968–3975 https://doi.org/10.1007/s00330-018-5706-6 ONCOLOGY Differentiation between pilocytic astrocytoma and glioblastoma: a decision tree model using contrast-enhanced magnetic resonance imaging-derived quantitative radiomic features Fei Dong1 & Qian Li1 & Duo Xu1 & Wenji Xiu2 & Qiang Zeng3 & Xiuliang Zhu1 & Fangfang Xu1 & Biao Jiang1 & Minming Zhang1 Received: 13 March 2018 /Revised: 8 July 2018 /Accepted: 6 August 2018 /Published online: 12 November 2018 # European Society of Radiology 2018 Abstract Objective To differentiate brain pilocytic astrocytoma (PA) from glioblastoma (GBM) using contrast-enhanced mag- netic resonance imaging (MRI) quantitative radiomic features by a decision tree model. Methods Sixty-six patients from two centres (PA, n = 31; GBM, n = 35) were randomly divided into training and validation data sets (about 2:1). Quantitative radiomic features of the tumours were extracted from contrast-enhanced MR images. A subset of features was selected by feature stability and Boruta algorithm. The selected features were used to build a decision tree model. Predictive accuracy, sensitivity and specificity were used to assess model performance. The classification outcome of the model was combined with tumour location, age and gender features, and multivariable logistic regression analysis and permutation test using the entire data set were performed to further evaluate the decision tree model. Results A total of 271 radiomic features were successfully extracted for each tumour. Twelve features were selected as input variables to build the decision tree model. Two features S(1, -1) Entropy and S(2, -2) SumAverg were finally included in the model. The model showed an accuracy, sensitivity and specificity of 0.87, 0.90 and 0.83 for the training data set and 0.86, 0.80 and 0.91 for the validation data set.
    [Show full text]
  • Choroid Plexus Tumors: a Review
    UC San Diego UC San Diego Previously Published Works Title Perinatal (fetal and neonatal) choroid plexus tumors: a review. Permalink https://escholarship.org/uc/item/0sm7q5q7 Journal Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 35(6) ISSN 0256-7040 Authors Crawford, John R Isaacs, Hart Publication Date 2019-06-01 DOI 10.1007/s00381-019-04135-x Peer reviewed eScholarship.org Powered by the California Digital Library University of California Child's Nervous System (2019) 35:937–944 https://doi.org/10.1007/s00381-019-04135-x REVIEW ARTICLE Perinatal (fetal and neonatal) choroid plexus tumors: a review John R. Crawford1,2,3 & Hart Isaacs Jr3,4 Received: 13 September 2018 /Accepted: 20 March 2019 /Published online: 5 April 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Introduction The object of this review is to describe the choroid plexus tumors (CPTs) occurring in the fetus and neonate with regard to clinical presentation, location, pathology, treatment, and outcome. Materials and methods Case histories and clinical outcomes were reviewed from 93 cases of fetal and neonatal tumors obtained from the literature and our own institutional experience from 1980 to 2016. Results Choroid plexus papilloma (CPP) is the most common tumor followed by choroid plexus carcinoma (CPC) and atypical choroid plexus papilloma (ACPP). Hydrocephalus and macrocephaly are the presenting features for all three tumors. The lateral ventricles are the main site of tumor origin followed by the third and fourth ventricles, respectively. CPTs of the fetus are detected most often near the end of the third trimester of pregnancy by fetal ultrasound.
    [Show full text]
  • Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations
    Published OnlineFirst July 13, 2018; DOI: 10.1158/1541-7786.MCR-17-0507 Genomics Molecular Cancer Research Desmoplastic Infantile Ganglioglioma/ Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations Anthony C. Wang1, David T.W. Jones2, Isaac Joshua Abecassis3, Bonnie L. Cole4, Sarah E.S. Leary5, Christina M. Lockwood6, Lukas Chavez2, David Capper7, Andrey Korshunov7, Aria Fallah1, Shelly Wang8, Chibawanye Ene3, James M. Olson5, J. Russell Geyer5, Eric C. Holland3, Amy Lee3, Richard G. Ellenbogen3, and Jeffrey G. Ojemann3 Abstract Desmoplastic infantile ganglioglioma (DIG) and desmo- transformation were found, and sequencing of the recurrence plastic infantile astrocytoma (DIA) are extremely rare tumors demonstrated a new TP53 mutation in one case, new ATRX that typically arise in infancy; however, these entities have not deletion in one case, and in the third case, the original tumor been well characterized in terms of genetic alterations or harbored an EML4–ALK fusion, also present at recurrence. clinical outcomes. Here, through a multi-institutional collab- DIG/DIA are distinct pathologic entities that frequently harbor V600 oration, the largest cohort of DIG/DIA to date is examined BRAF mutations. Complete surgical resection is the ideal using advanced laboratory and data processing techniques. treatment, and overall prognosis is excellent. While, the small Targeted DNA exome sequencing and DNA methylation sample size and incomplete surgical records limit a definitive profiling were performed on tumor specimens obtained from conclusion about the risk of tumor recurrence, the risk appears different patients (n ¼ 8) diagnosed histologically as DIG/ quite low. In rare cases with wild-type BRAF, malignant DIGA. Two of these cases clustered with other tumor entities, progression can be observed, frequently with the acquisition and were excluded from analysis.
    [Show full text]
  • Gliomatosis Cerebri with Neurofibromatosis: an Autopsy-Proven Case
    Child's Nerv Syst (1999) 15:219-221 © Springer-Verlag 1999 BRILF Önal Gliomatosis cerebri with neurofibromatosis: Çiçek an autopsy-proven case Gliomatosis cerebri Received: 15 July 1998 Abstract is a stereotactic ante-mortem diagnosis glial neoplastic process that is dif- and the other after autopsy. in this fusely distributed through neural paper. the autopsy-proven case Ç. Önal (BI) 1 • Ç. structures, whose anatomical config- of this rare disease with coexistent Department of Neurosurgery, uration remains Among the neurofibromatosis - the sixth lstanbul School of Medicine, more than 19,000 cases hospitalized case reported in the literature - Universitv of Istanbul, Çapa. Turkey in Istanbul University Istanbul is presented. School of Medicine Department of address: 1 Cad. Özenç Sok .. 4/9. Neurosurgery throughout the past Key words Gliomatosis cerebri · TR-81080 Erenköy-lstanbul. Turkey 45 years, only 2 cases were diag- Neurofibromatosis · Autopsy · Fax: +90-422-34 !O 726 nosed as gliomatosis cerebri. 1 by GFAP tened gyri showing diffuse oedema and no enhancement lntroduction (Fig. 1 Antibiotic and therapy was begun when the initial diagnosis of meningitis was made. No change was noted on Gliomatosis cerebri is a rare tumour of neuroepithelial or- follow-up CT performed 5 days later. MRI studie~ showed diffuse igin with vague presentation [l. 3. 5-8). Even hypo-isointense lesions in T1 and extensive lesions in with the aid T2-weighted and proton density tPDJ images (Figs. 2. 3). The me- of the most sophisticated techniques, ante-mortem diagno- dulla spinalis was in spite of an therapy. her condi- sis is difficult [2, 8).
    [Show full text]
  • The Genetic Landscape of Ganglioglioma Melike Pekmezci1, Javier E
    Pekmezci et al. Acta Neuropathologica Communications (2018) 6:47 https://doi.org/10.1186/s40478-018-0551-z RESEARCH Open Access The genetic landscape of ganglioglioma Melike Pekmezci1, Javier E. Villanueva-Meyer2, Benjamin Goode1, Jessica Van Ziffle1,3, Courtney Onodera1,3, James P. Grenert1,3, Boris C. Bastian1,3, Gabriel Chamyan4, Ossama M. Maher5, Ziad Khatib5, Bette K. Kleinschmidt-DeMasters6, David Samuel7, Sabine Mueller8,9,10, Anuradha Banerjee8,9, Jennifer L. Clarke10,11, Tabitha Cooney12, Joseph Torkildson12, Nalin Gupta8,9, Philip Theodosopoulos9, Edward F. Chang9, Mitchel Berger9, Andrew W. Bollen1, Arie Perry1,9, Tarik Tihan1 and David A. Solomon1,3* Abstract Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN.
    [Show full text]
  • Risk-Adapted Therapy for Young Children with Embryonal Brain Tumors, High-Grade Glioma, Choroid Plexus Carcinoma Or Ependymoma (Sjyc07)
    SJCRH SJYC07 CTG# - NCT00602667 Initial version, dated: 7/25/2007, Resubmitted to CPSRMC 9/24/2007 and 10/6/2007 (IRB Approved: 11/09/2007) Activation Date: 11/27/2007 Amendment 1.0 dated January 23, 2008, submitted to CPSRMC: January 23, 2008, IRB Approval: March 10, 2008 Amendment 2.0 dated April 16, 2008, submitted to CPSRMC: April 16, 2008, (IRB Approval: May 13, 2008) Revision 2.1 dated April 29, 2009 (IRB Approved: April 30, 2009 ) Amendment 3.0 dated June 22, 2009, submitted to CPSRMC: June 22, 2009 (IRB Approved: July 14, 2009) Activated: August 11, 2009 Amendment 4.0 dated March 01, 2010 (IRB Approved: April 20, 2010) Activated: May 3, 2010 Amendment 5.0 dated July 19, 2010 (IRB Approved: Sept 17, 2010) Activated: September 24, 2010 Amendment 6.0 dated August 27, 2012 (IRB approved: September 24, 2012) Activated: October 18, 2012 Amendment 7.0 dated February 22, 2013 (IRB approved: March 13, 2013) Activated: April 4, 2013 Amendment 8.0 dated March 20, 2014. Resubmitted to IRB May 20, 2014 (IRB approved: May 22, 2014) Activated: May 30, 2014 Amendment 9.0 dated August 26, 2014. (IRB approved: October 14, 2014) Activated: November 4, 2014 Un-numbered revision dated March 22, 2018. (IRB approved: March 27, 2018) Un-numbered revision dated October 22, 2018 (IRB approved: 10-24-2018) RISK-ADAPTED THERAPY FOR YOUNG CHILDREN WITH EMBRYONAL BRAIN TUMORS, HIGH-GRADE GLIOMA, CHOROID PLEXUS CARCINOMA OR EPENDYMOMA (SJYC07) Principal Investigator Amar Gajjar, M.D. Division of Neuro-Oncology Department of Oncology Section Coordinators David Ellison, M.D., Ph.D.
    [Show full text]
  • Pediatric and Adolescent Oligodendrogliomas
    Pediatric and Adolescent Oligodendrogliomas Harold Tice, 1 Patrick D. Barnes, 1 Liliana Goumnerova,2 R. Michael Scott,2 and Nancy J . Tarbell3 PURPOSE: To review the clinical and imaging findings in pediatric and adolescent intracranial pure oligodendrogliomas. METHODS: The clinical, CT, and MR data in 39 surgically proved pure oligodendrogliomas were retrospectively reviewed. RESULTS: The frontal or temporal lobes were involved in 32 (82%) cases. Seventy percent of the tumors were hypodense on CT, three-fourths were hypointense on T1-weighted images, and all were hyperintense on spin-density and T2- weighted images. Fewer than 40% of the lesions demonstrated calcification, and nearly 60% had well-defined margins. Mass effect was seen in fewer than half of the cases, and edema could be separately identified in only one case. Tumor enhancement was seen in fewer than 25%. In 39 cases after partial (3), subtotal (16), or total (20) resection, follow-up studies demonstrated stability over a mean period of 5 years. CONCLUSION: The findings in this pediatric series of pure oligodendrogliomas (without mixed cell elements) differ from previous adult series in that ca lcifi­ cation, contrast enhancement, and edema are seen less frequently. In addition, very slow or no growth is often characteristic, and these patients have an excellent prognosis with su rgical resection. Index terms: Oligodendroglioma; Brain, occipital lobe; Brain neoplasms, computed tomography; Brain neoplasms, magnetic resonance; Brain neoplasms, in infants and children; Pediatric neuro­ radiology AJNR 14:1293-1300, Nov /Dec 1993 Oligodendrogliomas comprise 4% to 7% of all eluded presentation, course, and the length of time from primary intracranial gliomas (1).
    [Show full text]