title: The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes.
abstract: Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFB-MYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed ≥1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML.
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Olsson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Zettermark
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biloglav
authors.affiliation: Department of Paediatrics, Skåne University Hospital, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Castor
authors.affiliation: Department of Paediatrics, Linköping University Hospital, Linköping, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Behrendtz
authors.affiliation: Department of Medical Bioscience, University of Umeå, Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D020732:Cytogenetic Analysis / Q000379:methods*; D005091:Exons / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
keywords: paediatric acute myeloid leukaemia; single nucleotide polymorphism array; targeted deep exon sequencing