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Kristian W Pajtler - One of the best experts on this subject based on the ideXlab platform.
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yap1 subgroup supratentorial Ependymoma requires tead and nuclear factor i mediated transcriptional programmes for tumorigenesis
Nature Communications, 2019Co-Authors: Kristian W Pajtler, Lei Zhang, Yiju Wei, Konstantin Okonechnikov, Patricia Benites Goncalves Da Silva, Mikaella Vouri, Sebastian Brabetz, Laura Sieber, Melissa GulleyAbstract:YAP1 fusion-positive supratentorial Ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human Ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive Ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of Ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
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diagnostics of pediatric supratentorial rela Ependymomas integration of information from histopathology genetics dna methylation and imaging
Brain Pathology, 2019Co-Authors: Kristian W Pajtler, Melanie Pages, Stephanie Puget, David Castel, Nathalie BoddaertAbstract:Ependymoma with RELA fusion has been defined as a novel entity of the revised World Health Organization 2016 classification of tumors of the central nervous system (CNS), characterized by fusion transcripts of the RELA gene and consequent pathological activation of the NFkB pathway. These tumors represent the majority of supratentorial Ependymomas in children. The validation of diagnostic tools to identify this clinically relevant Ependymoma entity is essential. Here, we have used interphase fluorescent in situ hybridization (FISH) for C11orf95 and RELA, immunohistochemistry (IHC) for p65-RelA and the recently developed DNA methylation-based classification besides conventional histopathology, and compared the precision of the methods in 40 supratentorial pediatric brain tumors diagnosed as Ependymomas in the past years. Reverse transcription PCR (RT-PCR) and RNA sequencing were performed to explore discordant cases. Furthermore, we integrated imaging and clinical features as additional layers of information. The concordance between nuclear RelA expression by IHC and RELA FISH was 100%. Concordance between IHC and DNA methylation profiling, and between FISH and DNA methylation profiling was also high (96.4% and 95.2%, respectively). Thirty-four out of 40 (85%) cases were confirmed by integrated diagnoses as ependymal tumors, including 22 RELA-fused Ependymomas (71% of ependymal tumors), two YAP1-fused Ependymomas (6%), six non-RELA/non-YAP1 Ependymomas (18%) and four ependymal/subependymal mixed tumors (12%). Ependymal/subependymal mixed tumors had an excellent clinical outcome despite the presence of histopathological signs of malignancy, suggesting that these tumors should not be diagnosed as classic Ependymomas. DNA methylation profiling helped in the differential diagnosis of RELA-fused Ependymomas. IHC and FISH, which are available in the majority of pathology laboratories, are valuable tools to identify RELA-fused Ependymomas.
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molecular heterogeneity and cxorf67 alterations in posterior fossa group a pfa Ependymomas
Acta Neuropathologica, 2018Co-Authors: Kristian W Pajtler, Ji Wen, Jensmartin Hubner, Wilda Orisme, Bo Tang, Martin Sill, Vijay Ramaswamy, Tong Lin, Sujuan JiaAbstract:Of nine Ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA Ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c Ependymomas showed an overall survival at 5 years of > 90%. Unlike other Ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this Ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA Ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA Ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA Ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA Ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.
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epidemiology molecular classification and who grading of Ependymoma
Journal of Neurosurgical Sciences, 2018Co-Authors: Jensmartin Hubner, Marcel Kool, Stefan M Pfister, Kristian W PajtlerAbstract:Ependymoma can arise throughout all compartments of the central nervous system with prevalence for intracranial and spinal location in children and adults, respectively. The current histopathology based WHO grading system distinguishes grade I, II 'classic', and III 'anaplastic' Ependymoma. However, analysis of multiple cohorts of intracranial Ependymoma demonstrate a wide variance in the utility of the grade II versus grade III distinction as a prognostic marker that may additionally be confounded by the anatomic compartment. Recent (epi)genomic profiling efforts have identified molecularly distinct groups of Ependymoma arising from all three anatomic compartments of the central nervous system that outperform the current histopathological classification regarding clinical associations. These advances have led to the cognition that molecular classification should be part of all future clinical trials in Ependymoma patients. Clinical management of intracranial Ependymomas (WHO Grade II/III) is challenging and molecular classification based risk stratification may help to intensify treatment and surveillance in high-risk patients but to de-escalate therapy in certain patient groups at low risk for recurrence. Finally, experience of neurosurgeons, and other disciplines, as well as intensified co-operation between all stakeholders involved hold promise to finally improve outcome of patients affected with Ependymoma.
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therapeutic targeting of Ependymoma as informed by oncogenic enhancer profiling
Nature, 2018Co-Authors: Stephen C Mack, Kristian W Pajtler, Konstantin Okonechnikov, Lukas Chavez, Kelsey C Bertrand, Xiuxing WangAbstract:Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial Ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa Ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa Ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial Ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). SubEpendymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary Ependymomas in two non-overlapping primary Ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of Ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.
James Dalton - One of the best experts on this subject based on the ideXlab platform.
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a de novo mouse model of c11orf95 rela fusion driven Ependymoma identifies driver functions in addition to nf κb
Cell Reports, 2018Co-Authors: Tatsuya Ozawa, Yoshie Yasui, Frank Szulzewsky, Sonali Arora, Gordana Juricsekhar, Yoshiteru Miyajima, Hamid Bolouri, Jason Barber, Robert Kupp, James DaltonAbstract:Summary The majority of supratentorial Ependymomas (ST-Ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELAFUS). Neural stem cells transduced with RELAFUS ex vivo form Ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELAFUS is sufficient to drive de novo Ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELAFUS drives ST-Ependymoma formation from periventricular neural stem cells in mice and that RELAFUS-induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB.
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c11orf95 rela fusions drive oncogenic nf kb signaling in Ependymoma
Neuro-oncology, 2014Co-Authors: Richard J Gilbertson, James Dalton, Matthew Parker, Kumarasamypet M Mohankumar, Chandanamali Punchihewa, Ricardo Weinlich, Ruth G Tatevossian, Timothy N Phoenix, Ryan P Lee, Radhika ThiruvenkatamAbstract:BACKGROUND: The nuclear factor-kB (NF-kB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kB activity in cancer. METHODS: To identify additional genetic alterations that drive Ependymoma, we sequenced the whole genomes (WGS) of 41 tumours and matched normal blood, and the transcriptomes (RNAseq) of 77 tumours. The transforming significance of alterations were tested in mouse NSCs that we showed previously to be cells of origin of Ependymoma. RESULTS: Here, we show that more than two thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kB target genes, and rapidly transformed neural stem cells—the cell of origin of Ependymoma—to form these tumours in mice. CONCLUSIONS: Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial Ependymoma. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.
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c11orf95 rela fusions drive oncogenic nf κb signalling in Ependymoma
Nature, 2014Co-Authors: Matthew Parker, James Dalton, Kumarasamypet M Mohankumar, Chandanamali Punchihewa, Ricardo Weinlich, Yongjin Li, Ruth G Tatevossian, Timothy N Phoenix, Radhika Thiruvenkatam, Elsie WhiteAbstract:Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95–RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95–RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of Ependymoma—to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial Ependymoma. At least two-thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of nuclear factor-κB (NF-κB) signalling, and uncharacterized gene C11orf95; C11orf95–RELA fusion proteins translocate spontaneously to the nucleus to activate NF-κB target genes, and rapidly transform neural stem cells to form tumours in mice In this issue of Nature two groups present independent genomic analyses on Ependymomas, a type of tumour that occurs throughout the nervous system, but most commonly in the hindbrain in children. Mack et al. found a low overall mutation rate and no significant recurrent mutations in 47 hindbrain Ependymomas. But posterior fossa group B tumours, a subgroup found predominantly in infants and associated with poor prognosis, were distinguished by a CpG island methylator phenotype. This subgroup is shown to be susceptible to various compounds that target epigenetic modifications, including an EZH2 inhibitor that showed efficacy in a mouse xenograft model. Parker et al. found the C11orf95–RELA fusion gene in about 70% of supratentorial tumours, but not in other Ependymoma subgroups. The gene fusions arise through chromothripsis and lead to the expression of a fusion protein that constitutively activates NF-κB signalling. In a mouse model, expression of C11orf95–RELA in neural stem cells leads to the formation of brain tumours. These findings identify NF-κB signalling as a possible therapeutic target in patients with this type of Ependymoma.
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c11orf95 rela fusions drive oncogenic nf κb signalling in Ependymoma
Nature, 2014Co-Authors: Matthew Parker, James Dalton, Kumarasamypet M Mohankumar, Chandanamali Punchihewa, Ricardo Weinlich, Ruth G Tatevossian, Timothy N Phoenix, Radhika Thiruvenkatam, Ryan P Lee, Elsie WhiteAbstract:Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of Ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial Ependymoma.
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distinct disease risk groups in pediatric supratentorial and posterior fossa Ependymomas
Acta Neuropathologica, 2012Co-Authors: Catherine Godfraind, James Dalton, Robert A Sanford, Thomas E Merchant, Mehmet Kocak, Joanna M Kaczmarska, Karen Wright, F A Boop, A Gajjar, David W EllisonAbstract:No reliable classification is in clinical use for the therapeutic stratification of children with Ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with Ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial Ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children's Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa Ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial Ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa Ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.
Elsie White - One of the best experts on this subject based on the ideXlab platform.
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c11orf95 rela fusions drive oncogenic nf κb signalling in Ependymoma
Nature, 2014Co-Authors: Matthew Parker, James Dalton, Kumarasamypet M Mohankumar, Chandanamali Punchihewa, Ricardo Weinlich, Yongjin Li, Ruth G Tatevossian, Timothy N Phoenix, Radhika Thiruvenkatam, Elsie WhiteAbstract:Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95–RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95–RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of Ependymoma—to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial Ependymoma. At least two-thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of nuclear factor-κB (NF-κB) signalling, and uncharacterized gene C11orf95; C11orf95–RELA fusion proteins translocate spontaneously to the nucleus to activate NF-κB target genes, and rapidly transform neural stem cells to form tumours in mice In this issue of Nature two groups present independent genomic analyses on Ependymomas, a type of tumour that occurs throughout the nervous system, but most commonly in the hindbrain in children. Mack et al. found a low overall mutation rate and no significant recurrent mutations in 47 hindbrain Ependymomas. But posterior fossa group B tumours, a subgroup found predominantly in infants and associated with poor prognosis, were distinguished by a CpG island methylator phenotype. This subgroup is shown to be susceptible to various compounds that target epigenetic modifications, including an EZH2 inhibitor that showed efficacy in a mouse xenograft model. Parker et al. found the C11orf95–RELA fusion gene in about 70% of supratentorial tumours, but not in other Ependymoma subgroups. The gene fusions arise through chromothripsis and lead to the expression of a fusion protein that constitutively activates NF-κB signalling. In a mouse model, expression of C11orf95–RELA in neural stem cells leads to the formation of brain tumours. These findings identify NF-κB signalling as a possible therapeutic target in patients with this type of Ependymoma.
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c11orf95 rela fusions drive oncogenic nf κb signalling in Ependymoma
Nature, 2014Co-Authors: Matthew Parker, James Dalton, Kumarasamypet M Mohankumar, Chandanamali Punchihewa, Ricardo Weinlich, Ruth G Tatevossian, Timothy N Phoenix, Radhika Thiruvenkatam, Ryan P Lee, Elsie WhiteAbstract:Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial Ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of Ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial Ependymoma.
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cross species genomics matches driver mutations and cell compartments to model Ependymoma
Nature, 2010Co-Authors: Robert A Johnson, Helen Poppleton, Kumarasamypet M Mohankumar, Elsie White, Karen Wright, David Finkelstein, Stanley Pounds, Vikki Rand, Sarah Leary, Christopher J EdenAbstract:Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human Ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in Ependymoma. To select cellular compartments most likely to give rise to subgroups of Ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial Ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of Ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this Ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.
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cross species genomics matches driver mutations and cell compartments to model Ependymoma
Nature, 2010Co-Authors: Robert A Johnson, Helen Poppleton, Kumarasamypet M Mohankumar, Elsie White, Karen Wright, David Finkelstein, Stanley Pounds, Vikki Rand, Sarah Leary, Christopher EdenAbstract:Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, Johnson et al. home in on mutations that are specific to individual tumour subgroups. In the course of their study, the authors generate the first mouse model of Ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups. Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, these authors home in on mutations that are specific to individual tumour subgroups. In doing so, they generate the first mouse model of Ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups. Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown1,2,3. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human Ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in Ependymoma. To select cellular compartments most likely to give rise to subgroups of Ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial Ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf−/− NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of Ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this Ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.
James Lowe - One of the best experts on this subject based on the ideXlab platform.
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copy number gain of 1q25 predicts poor progression free survival for pediatric intracranial Ependymomas and enables patient risk stratification a prospective european clinical trial cohort analysis on behalf of the children s cancer leukaemia group cclg societe francaise d oncologie pediatrique sfop and international society for pediatric oncology siop
Clinical Cancer Research, 2012Co-Authors: Johnpaul Kilday, Felipe Andreiuolo, Biswaroop Mitra, Caroline Domerg, Jennifer H Ward, Teresa Ostesoibanez, Audrey Mauguen, Pascale Varlet, Mariececile Le Deley, James LoweAbstract:Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric Ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial Ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 Ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children9s Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 ( n = 60) and BBSFOP ( n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent Ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56–4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22–7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts. Conclusions: This is the first study to validate a prognostic genomic marker for childhood Ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. Clin Cancer Res; 18(7); 2001–11. ©2012 AACR .
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copy number gain of 1q25 predicts poor progression free survival for pediatric intracranial Ependymomas and enables patient risk stratification a prospective european clinical trial cohort analysis on behalf of the children s cancer leukaemia group cclg societe francaise d oncologie pediatrique sfop and international society for pediatric oncology siop
Clinical Cancer Research, 2012Co-Authors: Johnpaul Kilday, Felipe Andreiuolo, Biswaroop Mitra, Caroline Domerg, Jennifer H Ward, Teresa Ostesoibanez, Audrey Mauguen, Pascale Varlet, Mariececile Le Deley, James LoweAbstract:Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric Ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial Ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 Ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children9s Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 ( n = 60) and BBSFOP ( n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent Ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56–4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22–7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts. Conclusions: This is the first study to validate a prognostic genomic marker for childhood Ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. Clin Cancer Res; 18(7); 2001–11. ©2012 AACR .
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pediatric Ependymoma biological perspectives
Molecular Cancer Research, 2009Co-Authors: Johnpaul Kilday, Ruman Rahman, Sara Dyer, Lee Ridley, James Lowe, Beth Coyle, Richard GrundyAbstract:Pediatric Ependymomas are enigmatic tumors that continue to present a clinical management challenge despite advances in neurosurgery, neuroimaging techniques, and radiation therapy. Difficulty in predicting tumor behavior from clinical and histological factors has shifted the focus to the molecular and cellular biology of Ependymoma in order to identify new correlates of disease outcome and novel therapeutic targets. This article reviews our current understanding of pediatric Ependymoma biology and includes a meta-analysis of all comparative genomic hybridization (CGH) studies done on primary Ependymomas to date, examining more than 300 tumors. From this meta-analysis and a review of the literature, we show that Ependymomas in children exhibit a different genomic profile to those in adults and reinforce the evidence that Ependymomas from different locations within the central nervous system (CNS) are distinguishable at a genomic level. Potential biological markers of prognosis in pediatric Ependymoma are assessed and the Ependymoma cancer stem cell hypothesis is highlighted with respect to tumor resistance and recurrence. We also discuss the shifting paradigm for treatment modalities in Ependymoma that target molecular alterations in tumor-initiating cell populations.
Felipe Andreiuolo - One of the best experts on this subject based on the ideXlab platform.
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Supratentorial clear cell Ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling
Neuro-Oncology, 2016Co-Authors: Dominique Figarella-branger, E Le Lechapt-zalcman, E Tabouret, Stephanie Jünger, André Maues De Paula, Corinne Bouvier, Carole Colin, Anne Jouvet, Fabien Forest, Felipe AndreiuoloAbstract:Clear cell Ependymoma is one of the 4 main histological subtypes of Ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial Ependymomas, including supratentorial (ST) Ependymomas with Yes-associated protein 1 fusion (YAP1), ST Ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa Ependymomas with balanced genome, and posterior fossa Ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of Ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.
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copy number gain of 1q25 predicts poor progression free survival for pediatric intracranial Ependymomas and enables patient risk stratification a prospective european clinical trial cohort analysis on behalf of the children s cancer leukaemia group cclg societe francaise d oncologie pediatrique sfop and international society for pediatric oncology siop
Clinical Cancer Research, 2012Co-Authors: Johnpaul Kilday, Felipe Andreiuolo, Biswaroop Mitra, Caroline Domerg, Jennifer H Ward, Teresa Ostesoibanez, Audrey Mauguen, Pascale Varlet, Mariececile Le Deley, James LoweAbstract:Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric Ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial Ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 Ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children9s Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 ( n = 60) and BBSFOP ( n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent Ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56–4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22–7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts. Conclusions: This is the first study to validate a prognostic genomic marker for childhood Ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. Clin Cancer Res; 18(7); 2001–11. ©2012 AACR .
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copy number gain of 1q25 predicts poor progression free survival for pediatric intracranial Ependymomas and enables patient risk stratification a prospective european clinical trial cohort analysis on behalf of the children s cancer leukaemia group cclg societe francaise d oncologie pediatrique sfop and international society for pediatric oncology siop
Clinical Cancer Research, 2012Co-Authors: Johnpaul Kilday, Felipe Andreiuolo, Biswaroop Mitra, Caroline Domerg, Jennifer H Ward, Teresa Ostesoibanez, Audrey Mauguen, Pascale Varlet, Mariececile Le Deley, James LoweAbstract:Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric Ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial Ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 Ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children9s Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 ( n = 60) and BBSFOP ( n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent Ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56–4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22–7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts. Conclusions: This is the first study to validate a prognostic genomic marker for childhood Ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. Clin Cancer Res; 18(7); 2001–11. ©2012 AACR .