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      Divergent clonal selection dominates medulloblastoma at recurrence.

      1 , 2 , 1 , 2 , 1 , 2 , 3 , 4 , 1 , 1 , 2 , 3 , 5 , 1 , 2 , 1 , 2 , 3 , 6 , 7 , 8 , 8 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 1 , 2 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 10 , 10 , 10 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 11 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 2 , 4 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 12 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 13 , 14 , 9 , 15 , 16 , 17 , 18 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 6 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 35 , 36 , 37 , 38 , 39 , 39 , 40 , 41 , 42 , 41 , 43 , 44 , 45 , 46 , 47 , 47 , 47 , 47 , 48 , 49 , 49 , 50 , 51 , 51 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 2 , 57 , 2 , 58 , 2 , 6 , 2 , 57 , 2 , 3 , 6 , 59 ,   60 , 61 , 62 , 63 , 64 , 64 , 64 , 64 , 65 , 66 , 9 , 9 , 67 , 4 , 68 , 9 , 13 , 69 , 57 , 70 , 9 , 13 , 1 , 2 , 3 , 6
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          Abstract

          The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

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          Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.

          Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets. Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals. Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
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            Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma.

            Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
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              Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells.

              Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.
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                Author and article information

                Journal
                Nature
                Nature
                1476-4687
                0028-0836
                Jan 21 2016
                : 529
                : 7586
                Affiliations
                [1 ] Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
                [2 ] The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
                [3 ] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
                [4 ] The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
                [5 ] Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, M5S 3E1, Germany.
                [6 ] Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
                [7 ] Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
                [8 ] Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
                [9 ] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
                [10 ] Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
                [11 ] Center for Stem Cell &Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
                [12 ] Clinical Genomics Research Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario 44195, Canada.
                [13 ] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
                [14 ] School of Computing Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
                [15 ] Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
                [16 ] Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
                [17 ] Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon 1099-023, Portugal.
                [18 ] Departments of Oncology and Neuro-Oncology, University Children's Hospital of Zurich, Zurich 8032, Switzerland.
                [19 ] Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
                [20 ] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
                [21 ] Brain Tumor Program, Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
                [22 ] Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404, USA.
                [23 ] Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah 84132, USA.
                [24 ] A I duPont Hospital for Children, Wilmington, Delaware 19803, USA.
                [25 ] Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
                [26 ] Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
                [27 ] Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
                [28 ] Departments of Neurosurgery, Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
                [29 ] Departments of Pediatrics, Cell &Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USA.
                [30 ] Department of Neurosurgery, NYU Langone Medical Center, New York, New York 10016, USA.
                [31 ] Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University, New York, New York 10032, USA.
                [32 ] Department of Pediatrics-Hematology and Oncology, Rainbow Babies &Children's Hospital and Department of Pediatrics-Hematology and Oncology, Case Western Reserve, Cleveland, Ohio 44106, USA.
                [33 ] Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, Italy.
                [34 ] Center for Neuropathology, Ludwig-Maximilians-Universität, Munich 81377, Germany.
                [35 ] Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech Republic.
                [36 ] AP-HP, Department of Neurosurgery, Necker-Enfants Malades Hospital, Université René Descartes, Paris 75743, France.
                [37 ] Signaling in Development and Brain Tumors, CNRS UMR 3347 / INSERM U1021, Institut Curie, Paris Cedex 5 91405, France.
                [38 ] Division of Hematology/Oncology, British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada.
                [39 ] Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Brazil, Rebeirao Preto, São Paulo 14049-900, Brazil.
                [40 ] Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales 2065, Australia.
                [41 ] Queensland Children's Medical Research Institute, Children's Health Queensland, Brisbane, Queensland 4029, Australia.
                [42 ] Division of Oncology, Children's Health Queensland, Brisbane, Queensland 4029, Australia.
                [43 ] UQ Child Health Research Centre, The University of Queensland, Brisbane 4029, Australia.
                [44 ] Pediatric Neuro-Oncology Program, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30307, USA.
                [45 ] Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
                [46 ] Department of Hematology &Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
                [47 ] Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea.
                [48 ] Institute for Neuropathology, University of Bonn D-53105, Germany.
                [49 ] Children's University Hospital of Essen D-45147, Germany.
                [50 ] Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea.
                [51 ] Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
                [52 ] Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
                [53 ] Department of Neurology, Vanderbilt Medical Center, Nashville, Tennessee 37232-8550, USA.
                [54 ] Department of Neurology, Children's National Medical Center, Washington DC 20010-2970, USA.
                [55 ] Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy.
                [56 ] U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy.
                [57 ] Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
                [58 ] Division of Pathology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
                [59 ] Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
                [60 ] Departments of Pediatrics, Neurology and Neurosurgery, University of California San Francisco, San Francisco, California 94158, USA.
                [61 ] School of Pharmacology, University of Wisconsin, Madison, Wisconsin 53715, USA.
                [62 ] Molecular &Cellular Biology Program, University of Iowa, Iowa City, Iowa 52242, USA.
                [63 ] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
                [64 ] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
                [65 ] Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.
                [66 ] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
                [67 ] Division of Hematology/Oncology, McGill University, Montreal, Quebec H2W 1S6., Canada.
                [68 ] McLaughlin Centre and Department of Molecular Genetics, Banting and Best Department of Medical Research and Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
                [69 ] Department of Molecular Biology &Biochemistry, Simon Fraser University, Burnaby, British Columbia M5G 1L7, Canada.
                [70 ] Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
                Article
                nature16478 NIHMS789824
                10.1038/nature16478
                4936195
                26760213
                22e929a1-2e7c-48b2-ad0f-93a9f73a6577
                History

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