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Amanda Saratsis - One of the best experts on this subject based on the ideXlab platform.
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Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma.
Acta neuropathologica communications, 2017Co-Authors: Tina Huang, Andrea Piunti, Ali Shilatifard, Rishi Lulla, Craig Horbinski, Tadanori Tomita, C. David James, Amanda SaratsisAbstract:Diffuse midline gliomas (including diffuse intrinsic pontine glioma, DIPG) are highly morbid glial neoplasms of the thalamus or brainstem that typically arise in young children and are not surgically resectable. These tumors are characterized by a high rate of histone H3 mutation, resulting in replacement of lysine 27 with methionine (K27M) in genes encoding H3 variants H3.3 (H3F3A) and H3.1 (HIST1H3B). Detection of these gain-of-function mutations has clinical utility, as they are associated with distinct tumor biology and clinical outcomes. Given the paucity of tumor tissue available for molecular analysis and relative morbidity of midline tumor biopsy, CSF-derived tumor DNA from patients with diffuse midline glioma may serve as a viable alternative for clinical detection of histone H3 mutation. We demonstrate the feasibility of two strategies to detect H3 mutations in CSF-derived tumor DNA from children with brain tumors (n = 11) via either targeted Sanger sequencing of H3F3A and HIST1H3B, or H3F3A c.83 A > T detection via nested PCR with mutation-specific primers. Of the six CSF specimens from children with diffuse midline glioma in our cohort, tumor DNA sufficient in quantity and quality for analysis was isolated from five (83%), with H3.3K27M detected in four (66.7%). In addition, H3.3G34V was identified in tumor DNA from a patient with supratentorial glioblastoma. Test sensitivity (87.5%) and specificity (100%) was validated via immunohistochemical staining and Sanger sequencing in available matched tumor tissue specimens (n = 8). Our results indicate that histone H3 gene mutation is detectable in CSF-derived tumor DNA from children with brain tumors, including diffuse midline glioma, and suggest the feasibility of “liquid biopsy” in lieu of, or to complement, tissue diagnosis, which may prove valuable for stratification to targeted therapies and monitoring treatment response.
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bt 01tenascin c a novel therapeutic target in pediatric brainstem glioma
Neuro-oncology, 2015Co-Authors: Amanda Saratsis, Madhuri Kambhampati, Jordan Hall, Roger J Packer, Mojca Stampar, Eric Raabe, Javad NazarianAbstract:INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is the most deadly solid tumor of childhood. Histone 3 mutation occurs in 80% of DIPGs, causing global transcriptional changes. Tenascin-C (TNC) is an extracellular matrix protein expressed during normal brain development by oligodendroglial progenitor cells (OPCs), the purported DIPG cell of origin. TNC is highly expressed in adult glioma, contributing to local invasion and poor survival. We report increased TNC in tumor tissue and cerebrospinal fluid (CSF) from children with high-grade glioma, including DIPG, and characterize TNC expression in relation to H3K27M mutation and DNA methylation status. METHODS: Tumor tissue collected intraoperatively or post-mortem from children with brainstem (DIPG, n = 14), supratentorial (n = 7), and cerebellar astrocytoma (n = 2), and CSF from DIPG (n = 9) and supratentorial astrocytoma (n = 17) was subjected to MS/MS proteomic analysis. Tissue gene expression, DNA methylation, H3F3A and HIST1H3B sequencing was performed. TNC expression was validated via Western blot and immunohistochemistry. Data integration was performed with Genome Studio, Partek and Ingenuity Pathway Analysis. RESULTS: TNC expression was significantly increased in 75% of gliomas compared to normal tissue, including all DIPG specimens tested (fold change >2, p < 0.05). Secreted TNC was detected in 7/9 DIPG CSF specimens (77.8%). Tumor-specific TNC expression was confirmed with Western blot and tissue immunohistochemistry. TNC expression correlated with tumor grade and was associated with Notch pathway activation, H3K27M mutation, and TNC promoter hypomethylation. CONCLUSIONS: We report increased TNC expression in tissue and CSF of pediatric high-grade gliomas, including DIPGs, associated with promoter hypomethylation and H3K27M mutation. Given the effect of TNC on OPC proliferation, migration and differentiation, TNC could serve as a clinical biomarker of disease and rational therapeutic target for a substantial subgroup of DIPG patients. Studies exploring the mechanism of TNC overexpression and effects of targeting TNC expression in DIPG are currently underway.
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comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes
Acta Neuropathologica, 2014Co-Authors: Amanda Saratsis, Eric H Raabe, Madhuri Kambhampati, Kendall Snyder, Sridevi Yadavilli, Joseph M Devaney, Brennan Harmon, Jordan Hall, Melanie WeingartAbstract:Diffuse intrinsic pontine glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh-frozen DIPG specimens (n = 14), normal brain tissue (n = 10), and other pediatric brain tumors (n = 17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of Clusterin (CLU), Elongation Factor 2 (EF2), and Talin-1 (TLN1) in DIPGs studied. Comparisons to mRNA expression profiles generated from tumor and adjacent normal brain tissue indicated two DIPG subgroups, characterized by upregulation of Myc (N-Myc) or Hedgehog (Hh) signaling. We validated upregulation of PTCH, a membrane receptor in the Hh signaling pathway, in a subgroup of DIPG specimens. DNA methylation analysis indicated global hypomethylation of DIPG compared to adjacent normal tissue specimens, with differential methylation of 24 genes involved in Hh and Myc pathways, correlating with protein and mRNA expression patterns. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77 % of our DIPG cohort. Supervised analysis revealed a unique methylation pattern in mutated specimens compared to the wild-type DIPG samples. This study presents the first comprehensive multidimensional protein, mRNA, and methylation profiling of pediatric brain tumor specimens, detecting the presence of two subgroups within our DIPG cohort. This multidimensional analysis of DIPG provides increased analytical power to more fully explore molecular signatures of DIPGs, with implications for evaluating potential molecular subtypes and biomarker discovery for assessing response to therapy.
Lindsey M Hoffman - One of the best experts on this subject based on the ideXlab platform.
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clinical radiologic pathologic and molecular characteristics of long term survivors of diffuse intrinsic pontine glioma dipg a collaborative report from the international and european society for pediatric oncology dipg registries
Journal of Clinical Oncology, 2018Co-Authors: Lindsey M Hoffman, Sophie Veldhuijzen E M Van Zanten, Niclas Colditz, Joshua Baugh, Brooklyn Chaney, Marion Hoffmann, Adam Lane, Christine FullerAbstract:Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
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spatial genomic heterogeneity in diffuse intrinsic pontine and midline high grade glioma implications for diagnostic biopsy and targeted therapeutics
Acta neuropathologica communications, 2016Co-Authors: Lindsey M Hoffman, Mariko Dewire, Scott Ryall, Pawel Buczkowicz, James L Leach, Lili Miles, Arun K Ramani, Michael Brudno, Shiva Senthil Kumar, Rachid DrissiAbstract:Diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization. Median age at diagnosis was 6.1 years (range: 2.9–23.3 years). Median overall survival was 13.2 months (range: 11.2–32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.
Christine Fuller - One of the best experts on this subject based on the ideXlab platform.
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characteristics of patients 10 years of age with diffuse intrinsic pontine glioma a report from the international dipg registry
Neuro-oncology, 2018Co-Authors: Craig Erker, Brooklyn Chaney, Adam Lane, Christine Fuller, Nancy Yanez Escorza, Raya Saab, Mark W Kieran, Roger J Packer, Javad Nazarian, Jane E MinturnAbstract:BACKGROUND DIPG generally occurs in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years [range 10-26.8]. Median OS was 13 [2-82] months. The 1-, 3- and 5- years OS was 61.9%, 3.7%, and 1.5%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P<0.01) and present with longer symptom duration (P<0.01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and one was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
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clinical radiologic pathologic and molecular characteristics of long term survivors of diffuse intrinsic pontine glioma dipg a collaborative report from the international and european society for pediatric oncology dipg registries
Journal of Clinical Oncology, 2018Co-Authors: Lindsey M Hoffman, Sophie Veldhuijzen E M Van Zanten, Niclas Colditz, Joshua Baugh, Brooklyn Chaney, Marion Hoffmann, Adam Lane, Christine FullerAbstract:Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
Arie Perry - One of the best experts on this subject based on the ideXlab platform.
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diffuse midline gliomas with histone h3 k27m mutation a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations
Brain Pathology, 2016Co-Authors: David A Solomon, Nalin Gupta, Matthew D Wood, Tarik Tihan, Andrew W Bollen, Joanna J Phillips, Arie PerryAbstract:Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)-like foci, neuropil-like islands, pilomyxoid features, ependymal-like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)-like areas. In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.
Nalin Gupta - One of the best experts on this subject based on the ideXlab platform.
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MR Imaging Correlates for Molecular and Mutational Analyses in Children with Diffuse Intrinsic Pontine Glioma.
AJNR. American journal of neuroradiology, 2020Co-Authors: Camilo Jaimes, Sridhar Vajapeyam, Douglas L. Brown, P.-c. Kao, Lianne Greenspan, Nalin Gupta, Liliana Goumnerova, P. Bandopahayay, Frank DuboisAbstract:BACKGROUND AND PURPOSE: Recent advances in molecular techniques have characterized distinct subtypes of diffuse intrinsic pontine gliomas. Our aim was the identification of MR imaging correlates of these subtypes. MATERIALS AND METHODS: Initial MRIs from subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Univariate Cox proportional hazards regression was used to test the association of imaging predictors with overall and progression-free survival. Wilcoxon rank sum, Kruskal-Wallis, and Fisher exact tests were used to compare imaging measures among groups. RESULTS: Fifty patients had biopsy and MR imaging. The median age at trial registration was 6 years (range, 3.3–17.5 years); 52% were female. On the basis of immunohistochemical results, 48 patients were assigned to 1 of 4 subgroups: 28 in MGMT–/epidermal growth factor receptor (EGFR)–, 14 in MGMT–/EGFR+, 3 in MGMT+/EGFR–, and 3 in MGMT+/EGFR+. Twenty-three patients had histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HIST1H3C. Enhancing tumor volume was near-significantly different across molecular subgroups (P = .04), after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different (P ≤ .048) between patients with H3F3A and HIST1H3B/C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters are correlated with molecular subgroups and mutations in children with diffuse intrinsic pontine gliomas.
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a pilot precision medicine trial for children with diffuse intrinsic pontine glioma pnoc003 a report from the pacific pediatric neuro oncology consortium
International Journal of Cancer, 2019Co-Authors: Sabine Mueller, Nalin Gupta, Payal Jain, Winnie S Liang, Lindsay Kilburn, Cassie Kline, Eshini Panditharatna, Suresh N Magge, Bo Zhang, Yuankun ZhuAbstract:This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.
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diffuse midline gliomas with histone h3 k27m mutation a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations
Brain Pathology, 2016Co-Authors: David A Solomon, Nalin Gupta, Matthew D Wood, Tarik Tihan, Andrew W Bollen, Joanna J Phillips, Arie PerryAbstract:Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)-like foci, neuropil-like islands, pilomyxoid features, ependymal-like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)-like areas. In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.