Meta-analysis of Neuroblastomas Reveals a Skewed <i>ALK</i> Mutation Spectrum in Tumors with <i>MYCN</i> Amplification
Sara De BrouwerAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedKatleen De PreterAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedCandy KumpsAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedPiotr ZabrockiAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedMichaël PorcuAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedEllen M. WesterhoutAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedArjan LakemanAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedJo VandesompeleAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedJasmien HoebeeckAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedTom Van MaerkenAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedAnne De PaepeAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedGeneviève LaureysAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedJohannes H. SchulteAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedAlexander SchrammAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedCaroline Van den BroeckeAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedJoëlle VermeulenAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedNadine Van RoyAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedKlaus BeiskeAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedMarleen RenardAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedRosa NogueraAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedOlivier DelattreAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedIsabelle Janoueix‐LeroseyAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedPer KognerAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedTommy MartinssonAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedAkira NakagawaraAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedMiki OhiraAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedHuib N. CaronAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedAngelika EggertAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedJan CoolsAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedRogier VersteegAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, SwedFrank SpelemanAuthors' Affiliations: 1Center for Medical Genetics, 2Department of Paediatric Haematology and Oncology, and 3Department of Pathology, Ghent University Hospital, Ghent, Belgium; 4Department of Molecular and Developmental Genetics, K.U.Leuven-VIB, and 5Department of Paediatrics, University Hospital Leuven, Leuven, Belgium; 6Department of Human Genetics, Academic Medical Center, University of Amsterdam, and 7Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; 8Division of Hematology and Oncology, University Children's Hospital Essen, Essen, Germany; 9Department of Pathology, Rikshospitalet, Oslo, Norway; 10Department of Pathology, Medical School of Valencia, University of Valencia, Valencia, Spain; 11INSERM U830, Institut Curie, Paris, France; 12Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden; 13Department of Clinical Genetics, Gothenburg University, Gothenburg, Swed
2010en
ABI
Annotatsiya
PURPOSE: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression. EXPERIMENTAL DESIGN: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis. RESULTS: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival. CONCLUSIONS: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants.
Hali tarjima qilinmagan
Identifikatorlar
Iqtiboslar va manbalar
2 ta iqtibos0 ta foydalanilgan manba