title: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents.
abstract: Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium, Freiburg, Germany, and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hirabayashi
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Victor
authors.initials: V
authors.lastname: Pastor
authors.affiliation: Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic;
authors.forename: Jan
authors.initials: J
authors.lastname: Starý
authors.affiliation: Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark;
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.affiliation: Department of Pediatric Oncology and Hematology, University of Bologna, Bologna, Italy;
authors.forename: Riccardo
authors.initials: R
authors.lastname: Masetti
authors.affiliation: St. Anna Children's Hospital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria;
authors.forename: Michael
authors.initials: M
authors.lastname: Dworzak
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, Zurich, Switzerland;
authors.forename: Markus
authors.initials: M
authors.lastname: Schmugge
authors.affiliation: Erasmus Medical Center, Rotterdam, and Dutch Childhood Oncology Group, The Hague, The Netherlands;
authors.forename: Marry
authors.initials: M
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Pediatric Hematology, Oncology, and BMT, Medical University of Wroclaw, Wroclaw, Poland;
authors.forename: Marek
authors.initials: M
authors.lastname: Ussowicz
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Department of Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Spain;
authors.forename: Albert
authors.initials: A
authors.lastname: Catala
authors.affiliation: Paediatric Oncology and Haematology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland;
authors.forename: Owen P
authors.initials: OP
authors.lastname: Smith
authors.affiliation: Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic;
authors.forename: Petr
authors.initials: P
authors.lastname: Sedlacek
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.affiliation: Pediatric Hematology-Oncology, Fondazione Istituti di ricovero e cura a carattere scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;
authors.forename: Victoria
authors.initials: V
authors.lastname: Bordon
authors.affiliation: St. Anna Children's Hospital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria;
authors.forename: Susanne
authors.initials: S
authors.lastname: Matthes-Martin
authors.affiliation: Pediatric Oncology, Queen Silvias Children's Hospital, Gothenburg, Sweden;
authors.forename: Jonas
authors.initials: J
authors.lastname: Abrahamsson
authors.affiliation: Pediatric Oncology, Charité-University Medicine Berlin, Berlin, Germany;
authors.forename: Jörn Sven
authors.initials: JS
authors.lastname: Kühl
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany;
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.affiliation: Department of Pediatric Hematology and Oncology, Dr.v.Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzien
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Institute of Pathology, University of Erlangen, Erlangen, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany;
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Annámaria
authors.initials: A
authors.lastname: Cseh
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Noellke
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Ayami
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Rome, University of Pavia, Pavia, Italy; and.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Pathology, Clinical Center, Böblingen, Germany.
authors.forename: Irith
authors.initials: I
authors.lastname: Baumann
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Strahm
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium, Freiburg, Germany, and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics; D005260:Female; D050989:GATA2 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D009190:Myelodysplastic Syndromes / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D015983:Selection Bias; D055815:Young Adult
chemical_list: D050989:GATA2 Transcription Factor