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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 29 July 2014, Vol.111(30), pp.11061-6
    Description: Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.
    Keywords: Gtpase-Activating Proteins -- Metabolism ; Kruppel-Like Transcription Factors -- Metabolism ; Medulloblastoma -- Metabolism ; Nuclear Proteins -- Metabolism ; Transcription Factors -- Metabolism ; Zebrafish -- Metabolism ; Zebrafish Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Tumors ; Standardization ; Data Processing ; Classification ; Methylation ; Brain Cancer ; Bioinformatics ; Cancer ; Generalized Linear Models ; DNA Methylation ; Diagnosis ; Tumors ; Genomes ; Classification ; Central Nervous System ; Central Nervous System ; Diagnosis ; Cancer ; Learning Algorithms ; Diagnostic Software ; Data Processing ; Tumors ; Central Nervous System ; Gene Expression ; Standardization ; Classification ; Cancer ; Classifiers ; Classification ; Clinical Trials ; Deoxyribonucleic Acid–DNA ; Probability ; Diagnostic Systems ; Nervous System ; Methylation ; Data Processing ; Tumors ; Data Processing ; Deoxyribonucleic Acid–DNA ; Deoxyribonucleic Acid–DNA ; World Health Organization;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, July 29, 2014, Vol.111(30), p.11061(6)
    Description: Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are upregulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers. www.pnas.org/cgi/doi/10.1073/pnas.1322362111
    Keywords: Genes -- Research ; Genes -- Physiological Aspects ; Transcription Factors -- Physiological Aspects ; Transcription Factors -- Research ; Carcinogenesis -- Research ; Carcinogenesis -- Genetic Aspects
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
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  • 4
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
  • 6
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.2696-2696
    Description: CNS-primitive neuroectodermal tumors (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 323 fresh-frozen or paraffin-embedded institutionally diagnosed CNS-PNETs using DNA methylation and expression arrays. Data were compared to 211 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities.
    Keywords: Brain Tumors ; Differentiation ; Central Nervous System ; Data Processing ; Classification ; Pediatrics ; Adolescence ; DNA Methylation ; Nervous System Diseases ; Children ; Neurology & Neuropathology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.3084-3084
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 8
    Language: English
    In: International Journal of Cancer, 01 June 2013, Vol.132(11), pp.2714-2719
    Description: Breast cancer is a heterogeneous disease at both the clinical and molecular levels. This heterogeneity may give rise to different therapy responses. Molecular profiling has facilitated identification of signatures for stratifying patients who would potentially benefit from given therapies. Previously, we reported on a subset of genes with the potential for predicting response of primary breast cancer to neoadjuvant chemotherapy. Herein, we report that patients with luminal (estrogen receptor α [ERα]‐expressing) breast cancer were enriched for nonresponders. To identify novel factors that contribute to the survival of breast cancer cells, a loss‐of‐function screen was performed with a subset of genes overexpressed in patients with disease resistant to chemotherapy. This approach led us to identify protein phosphatase 1, regulatory subunit 15B (PPP1R15B) as a factor with a potentially essential role in the survival of ERα‐positive breast cancer cells. Functional analyses showed that PPP1R15B depletion results in impaired proliferation due to unsuccessful transition of cells from G1 to S phase of the cell cycle, and apoptosis induction. Moreover, our data revealed a regulatory role for PPP1R15B in activating ERα. Furthermore, a high level of mRNA expression was associated with poor outcome following tamoxifen‐based therapy. Accordingly, knockdown of PPP1R15B expression sensitized tamoxifen‐resistant MCF‐7 breast cancer cells to tamoxifen while reducing ERα abundance in these cells. Our findings reveal a novel role for PPP1R15B in the survival and therapy response of ERα‐positive breast cancer and may open new avenues for tumor subtype‐specific therapeutic strategies in the era of personalized medicine. While dysfunction of apoptotic pathways and uncontrolled cell proliferation have been shown to contribute to unsuccessful therapy in cancer, not all of the factors involved in the deregulation of these processes are known. Here the authors set to identify novel factors that contribute to the survival of breast cancer cells in patients with disease resistant to chemotherapy. The findings reveal a novel role for protein phosphatase 1, regulatory subunit 15B (PPP1R15B) in the survival and therapy response of ERα‐positive breast cancer and may open new avenues for tumor subtype‐specific therapeutic strategies in the era of personalized medicine.
    Keywords: Ppp1r15b ; Breast Cancer ; Estrogen Receptor Α ; Tamoxifen ; Drug Resistance ; Cell Proliferation
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 9
    Language: English
    In: Quick submit: 2017-02-07T23:04:35-0500
    Description: Glioma brain tumors that carry mutant copies of the IDH gene can be subdivided into two major classes. However, the development of and differences between these two classes are not well characterized. Venteicher et al. coupled bulk sequencing and publicly available data with single-cell RNA sequencing data on glioma patient tissue samples. They identified a common lineage program that is shared between glioma subtypes. This suggests that the observed differences between the two glioma classes originate from lineage-specific genetic changes and the tumor microenvironment. Science, this issue p. eaai8478 Tumor fitness, evolution, and resistance to therapy are governed by selection of malignant cells with specific genotypes, by expression programs related to cellular phenotypes, and by influences of the tumor microenvironment (TME). Although bulk tumor analysis can interrogate the genetic state of tumor cells with high precision, bulk expression profiles average the diverse cells within each tumor, thereby masking critical differences and providing limited insight into cancer cell programs and TME influences. Single-cell RNA sequencing (scRNA-seq) can help to address those challenges but incurs financial and logistic considerations, including the time required to accrue large cohorts of fresh tumor specimen for single-cell analysis. We reasoned that scRNA-seq of a limited number of representative tumors could be combined with bulk data from large cohorts to decipher differences between tumor subclasses. In this approach, bulk samples collected for large cohorts, such as from The Cancer Genome Atlas (TCGA), are first used to define the combined effects of differences in cancer cell genotypes, phenotypes, and the composition of the TME. Single-cell analysis of a limited set of representative tumors is then used to distinguish those effects. We applied this approach to understand the differences between two types of isocitrate dehydrogenase (IDH)-mutant gliomas: astrocytoma (IDH-A) and oligodendroglioma (IDH-O). IDH-A and IDH-O are distinguished by co-occurring signature genetic events and by histopathology and are thought to recapitulate distinct glial lineages. By combining 9879 scRNA-seq profiles from 10 IDH-A tumors, 4347 scRNA-seq profiles from six IDH-O tumors, and 165 TCGA bulk RNA profiles, we could decipher differences between these two tumor types at single-cell resolution. We find that differences in bulk expression profiles between IDH-A and IDH-O are primarily explained by the impact of signature genetic events and TME composition, but not by distinct expression programs of glial lineages in the malignant cells. We infer that both IDH-A and IDH-O share the same developmental hierarchy, consisting in each case of three subpopulations of malignant cells: nonproliferating cells differentiated along the astrocytic and oligodendrocytic lineages, and proliferative undifferentiated cells that resemble neural stem/progenitor cells. By analyzing tumors of different clinical grades, we observe that higher-grade tumors present enhanced proliferation, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia programs in the TME. Our approach provides a general framework to decipher differences between classes of human tumors by decoupling cancer cell genotypes, phenotypes, and the composition of the TME. The shared glial lineages and developmental hierarchies observed in IDH-A and IDH-O suggest a common progenitor for all IDH-mutant gliomas, shedding light on a long-standing debate in gliomagenesis. In contrast to the similarity in glial lineages, IDH-A and IDH-O differ significantly in their TME, and in particular in the abundance of microglia/macrophage cells. Microglia and macrophages also differ between IDH-A tumors of different grades. Our study redefines the cellular composition of human IDH-mutant gliomas, with important implications for disease management. (Top ) Human samples were dissociated and analyzed by scRNA-seq. (Bottom ) IDH-O and IDH-A differ in genetics and TME but are both primarily composed of three main types of malignant cells: cycling stem-like cells and noncycling astrocyte-like and oligodendrocyte-like cells. Tumor progression is associated with increased proliferation, decreased differentiation, and increase in macrophages over microglia in the TME. Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
    Keywords: Neural Stem Cells ; Brain Tumors ; Isocitrate Dehydrogenase ; Microglia ; Brain Cancer ; Brain ; Cancer ; Genomes ; Cell Proliferation ; Astrocytoma ; Histopathology ; Genotypes ; Oligodendroglioma ; Macrophages ; Dehydrogenases ; Glioma Cells ; Tumor Cells ; Dehydrogenase ; Genotypes ; Pools ; Brain Tumors ; Genetics ; Subpopulations ; Fitness ; Tumors ; Idh Gene ; Subpopulations ; Ribonucleic Acid–RNA ; Ribonucleic Acid–RNA;
    ISSN: Venteicher, Andrew S., Itay Tirosh, Christine Hebert, Keren Yizhak, Cyril Neftel, Mariella G. Filbin, Volker Hovestadt, et al. 2017. “Decoupling Genetics, Lineages, and Microenvironment in IDH-Mutant Gliomas by Single-Cell RNA-Seq.” Science 355 (6332) (March 30): eaai8478. doi:10.1126/science.aai8478.
    ISSN: 0036-8075
    E-ISSN: 10959203
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  • 10
    In: Nature, 2017, Vol.547(7663), p.311
    Description: Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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