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Nat Commun. 2017 Dec 19;8(1):2126. doi: 10.1038/s41467-017-02177-w.

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

Author information

1
Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany. d.lipka@dkfz.de.
2
Department of Hematology and Oncology, Medical Center, Otto-von-Guericke-University, Leipziger Strasse 44, 39120, Magdeburg, Germany. d.lipka@dkfz.de.
3
Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Leipziger Strasse 44, 39120, Magdeburg, Germany. d.lipka@dkfz.de.
4
Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany.
5
Cancer Epigenetics Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany.
6
Computational Epigenomics Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany.
7
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany.
8
Division of Biostatistics, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany.
9
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.
10
German Cancer Consortium (DKTK), 79106, Freiburg, Germany.
11
Division of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Hugstetter Strasse 55, 79106, Freiburg, Germany.
12
Institute of Molecular Medicine and Cell Research, University of Freiburg, Stefan-Meier-Strasse 17, 79104, Freiburg, Germany.
13
Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
14
German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
15
Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, INF 410, 69120, Heidelberg, Germany.
16
Department of Hematology and Oncology, Hospital Sant Joan de Déu, Passeig de Sant Joan de Déu, 2, 08950, Esplugues de Llobrega, Barcelona, Spain.
17
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.
18
St. Anna Children's Hospital and Children's Cancer Research Institute, Medical University of Vienna, Zimmermannplatz 10, 1090, Vienna, Austria.
19
Department of Pediatrics, Aarhus University Hospital Skejby, Palle Juul-Jensens Boulevard 82, 8200, Aarhus, Denmark.
20
Department of Pediatric Hematology and Oncology, Bambino Gesú Children's Hospital, University of Pavia, Piazza S. Onofrio 4, Rome, 00165, Italy.
21
Department of Pediatric Oncology and Hematology, University of Bologna, Via Massarenti 11, 40138, Bologna, Italy.
22
Department of Hematology and Oncology, University Children's Hospital, Steinwiesstrasse 75, 8032, Zurich, Switzerland.
23
Department of Paediatric Oncology and Haematology, Our Lady's Children's Hospital Crumlin, Dublin, 12, Ireland.
24
Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, V Úvalu 84, 150 06, Prague 5, Czech Republic.
25
Department of Pediatric Hematology, Oncology and BMT, Wroclaw Medical University, ul. Borowska 213, 50-556, Wroclaw, Poland.
26
Princess Maxima Center for Pediatric Oncology, Lundlaan 6, 3584, EA, Utrecht, The Netherlands.
27
Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
28
Cancer Epigenetics Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany. c.plass@dkfz.de.
29
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. c.plass@dkfz.de.

Abstract

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.

PMID:
29259247
PMCID:
PMC5736667
DOI:
10.1038/s41467-017-02177-w
[Indexed for MEDLINE]
Free PMC Article

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