Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup
Por:
Ramamoorthy S, Lebrecht D, Schanze D, Schanze I, Wieland I, Andrieux G, Metzger P, Hess M, Albert MH, Borkhardt A, Bresters D, Buechner J, Català-Temprano A, De Haas V, Dworzak M, Erlacher M, Hasle H, Jahnukainen K, Locatelli F, Masetti R, Stary J, Turkiewicz D, Vinci L, Wlodarski MW, Yoshimi A, Boerries M, Niemeyer CM, Zenker M and Flotho C
Publicada:
1 feb 2024
Ahead of Print:
1 nov 2023
Resumen:
Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1.
Filiaciones:
Ramamoorthy S:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Lebrecht D:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Schanze D:
Human Genetics, University of Magdeburg, Magdeburg, Germany
Schanze I:
Human Genetics, University of Magdeburg, Magdeburg, Germany
Wieland I:
Human Genetics, University of Magdeburg, Magdeburg, Germany
Andrieux G:
Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Metzger P:
Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Hess M:
Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Faculty of Biology, University of Freiburg, Freiburg, Germany
Albert MH:
Department of Pediatric Hematology and Oncology, Dr. v. Hauner Children's Hospital, University Hospital, LMU, Munich, Germany
Borkhardt A:
Department of Pediatric Oncology, Hematology and Immunology, University of Dusseldorf, Dusseldorf, Germany
Bresters D:
Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
Buechner J:
Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway
Català-Temprano A:
Department of Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain
De Haas V:
Diagnostic Laboratory/DCOG Laboratory, Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
Dworzak M:
St. Anna Children's Cancer Research Institute, Vienna, Austria
Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria
Erlacher M:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Freiburg, Freiburg, Germany
Hasle H:
Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark
Jahnukainen K:
Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Hospital, Helsinki, Finland
Locatelli F:
Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Catholic University of the Sacred Heart, Rome, Italy
Masetti R:
Pediatric Oncology and Hematology Unit "Lalla Seràgnoli", IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Stary J:
Department of Pediatric Hematology/ Oncology, Charles University and Univ Hospital Motol, Prague, Czech Republic
Turkiewicz D:
Department of Pediatric Oncology/Hematology, Skåne University Hospital, Lund, Sweden
Vinci L:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Wlodarski MW:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Yoshimi A:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Boerries M:
Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Freiburg, Freiburg, Germany
Niemeyer CM:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Freiburg, Freiburg, Germany
Zenker M:
Human Genetics, University of Magdeburg, Magdeburg, Germany
Flotho C:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Freiburg, Freiburg, Germany
Green Submitted, hybrid
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