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  • 1
    Keywords: GENES ; MOUSE ; SUBGROUPS ; GLIOBLASTOMA ; INTRINSIC PONTINE GLIOMAS ; HISTONE H3.3 ; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA ; BMP RECEPTOR ; I RECEPTOR ; ALK2
    Abstract: Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
    Type of Publication: Journal article published
    PubMed ID: 24705250
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  • 2
    Abstract: Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
    Type of Publication: Journal article published
    PubMed ID: 28394352
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    Publication Date: 2016-05-14
    Description: Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Chao -- Jain, Siddhant U -- Hoelper, Dominik -- Bechet, Denise -- Molden, Rosalynn C -- Ran, Leili -- Murphy, Devan -- Venneti, Sriram -- Hameed, Meera -- Pawel, Bruce R -- Wunder, Jay S -- Dickson, Brendan C -- Lundgren, Stefan M -- Jani, Krupa S -- De Jay, Nicolas -- Papillon-Cavanagh, Simon -- Andrulis, Irene L -- Sawyer, Sarah L -- Grynspan, David -- Turcotte, Robert E -- Nadaf, Javad -- Fahiminiyah, Somayyeh -- Muir, Tom W -- Majewski, Jacek -- Thompson, Craig B -- Chi, Ping -- Garcia, Benjamin A -- Allis, C David -- Jabado, Nada -- Lewis, Peter W -- DP2CA174499/CA/NCI NIH HHS/ -- DP2OD007447/OD/NIH HHS/ -- K08CA151660/CA/NCI NIH HHS/ -- K08CA181475/CA/NCI NIH HHS/ -- P01CA196539/CA/NCI NIH HHS/ -- P30CA008748/CA/NCI NIH HHS/ -- R01GM110174/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2016 May 13;352(6287):844-9. doi: 10.1126/science.aac7272.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. ; Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA. ; Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. ; Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Chemistry, Princeton University, Princeton, NJ 08544, USA. ; Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Surgical Oncology and Division of Orthopedic Surgery, Princess Margaret Hospital, University of Toronto, Toronto, Ontario M5T 2M9, Canada. ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. ; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA. ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada. ; Department of Medical Genetics and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada. ; Division of Orthopaedic Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. ; Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu. ; Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. Department of Pediatrics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu. ; Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27174990" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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