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RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

DB. Lipka, T. Witte, R. Toth, J. Yang, M. Wiesenfarth, P. Nöllke, A. Fischer, D. Brocks, Z. Gu, J. Park, B. Strahm, M. Wlodarski, A. Yoshimi, R. Claus, M. Lübbert, H. Busch, M. Boerries, M. Hartmann, M. Schönung, U. Kilik, J. Langstein, JA....

. 2017 ; 8 (1) : 2126. [pub] 20171219

Language English Country England, Great Britain

Document type Clinical Trial, Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19001027

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

Cancer Epigenetics Group Division of Epigenomics and Cancer Risk Factors German Cancer Research Center 69120 Heidelberg Germany

Cancer Epigenetics Group Division of Epigenomics and Cancer Risk Factors German Cancer Research Center INF 280 69120 Heidelberg Germany

Computational Epigenomics Group Division of Epigenomics and Cancer Risk Factors German Cancer Research Center INF 280 69120 Heidelberg Germany

Department of Hematology and Oncology Hospital Sant Joan de Déu Passeig de Sant Joan de Déu 2 08950 Esplugues de Llobrega Barcelona Spain

Department of Hematology and Oncology University Children's Hospital Steinwiesstrasse 75 8032 Zurich Switzerland

Department of Hematology Oncology and Rheumatology Heidelberg University Hospital INF 410 69120 Heidelberg Germany

Department of Paediatric Oncology and Haematology Our Lady's Children's Hospital Crumlin Dublin 12 Ireland

Department of Pediatric Hematology and Oncology Bambino Gesú Children's Hospital University of Pavia Piazza S Onofrio 4 Rome 00165 Italy

Department of Pediatric Hematology and Oncology Charles University and University Hospital Motol 5 Úvalu 84 150 06 Prague 5 Czech Republic

Department of Pediatric Hematology Oncology and BMT Wroclaw Medical University ul Borowska 213 50 556 Wroclaw Poland

Department of Pediatric Hematology Oncology and Stem Cell Transplantation Ghent University Hospital De Pintelaan 185 9000 Ghent Belgium

Department of Pediatric Oncology and Hematology University of Bologna Via Massarenti 11 40138 Bologna Italy

Department of Pediatrics Aarhus University Hospital Skejby Palle Juul Jensens Boulevard 82 8200 Aarhus Denmark

Division of Biostatistics German Cancer Research Center INF 280 69120 Heidelberg Germany

Division of Hematology Oncology and Stem Cell Transplantation University Medical Center Hugstetter Strasse 55 79106 Freiburg Germany

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical Center Faculty of Medicine University of Freiburg Heiliggeiststrasse 1 79106 Freiburg Germany

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical Center Faculty of Medicine University of Freiburg Heiliggeiststrasse 1 79106 Freiburg Germany German Cancer Consortium 79106 Freiburg Germany

Division of Theoretical Bioinformatics 69120 Heidelberg Germany

Division of Theoretical Bioinformatics INF 280 69120 Heidelberg Germany

Institute of Molecular Medicine and Cell Research University of Freiburg Stefan Meier Strasse 17 79104 Freiburg Germany German Cancer Consortium 69120 Heidelberg Germany

Institute of Molecular Medicine and Cell Research University of Freiburg Stefan Meier Strasse 17 79104 Freiburg Germany Lübeck Institute of Experimental Dermatology University of Lübeck Ratzeburger Allee 160 23562 Lübeck Germany

Princess Maxima Center for Pediatric Oncology Lundlaan 6 3584 EA Utrecht The Netherlands

Regulation of Cellular Differentiation Group Division of Epigenomics and Cancer Risk Factors German Cancer Research Center INF 280 69120 Heidelberg Germany

Regulation of Cellular Differentiation Group Division of Epigenomics and Cancer Risk Factors German Cancer Research Center INF 280 69120 Heidelberg Germany Department of Hematology and Oncology Medical Center Otto von Guericke University Leipziger Strasse 44 39120 Magdeburg Germany Health Campus Immunology Infectiology and Inflammation Otto von Guericke University Leipziger Strasse 44 39120 Magdeburg Germany

St Anna Children's Hospital and Children's Cancer Research Institute Medical University of Vienna Zimmermannplatz 10 1090 Vienna Austria

References provided by Crossref.org

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