title: Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia.
abstract: BACKGROUND
  Several studies of pediatric acute myeloid leukemia have described the various type-I or type-II aberrations and their relationship with clinical outcome. However, there has been no recent comprehensive overview of these genetic aberrations in one large pediatric acute myeloid leukemia cohort.
  
  
  METHODS
  We studied the different genetic aberrations, their associations and their impact on prognosis in a large pediatric acute myeloid leukemia series (n=506). Karyotypes were studied, and hotspot regions of NPM1, CEPBA, MLL, WT1, FLT3, N-RAS, K-RAS, PTPN11 and KIT were screened for mutations of available samples. The mutational status of all type-I and type-II aberrations was available in 330 and 263 cases, respectively. Survival analysis was performed in a subset (n=385) treated on consecutive acute myeloid leukemia Berlin-Frankfurt-Munster Study Group and Dutch Childhood Oncology Group treatment protocols.
  
  
  RESULTS
  Genetic aberrations were associated with specific clinical characteristics, e.g. significantly higher diagnostic white blood cell counts in MLL-rearranged, WT1-mutated and FLT3-ITD-positive acute myeloid leukemia. Furthermore, there was a significant difference in the distribution of these aberrations between children below and above the age of two years. Non-random associations, e.g. KIT mutations with core-binding factor acute myeloid leukemia, and FLT3-ITD with t(15;17)(q22;q21), NPM1- and WT1-mutated acute myeloid leukemia, respectively, were observed. Multivariate analysis revealed a 'favorable karyotype', i.e. t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22). NPM1 and CEBPA double mutations were independent factors for favorable event-free survival. WT1 mutations combined with FLT3-ITD showed the worst outcome for 5-year overall survival (22±14%) and 5-year event-free survival (20±13%), although it was not an independent factor in multivariate analysis.
  
  
  CONCLUSIONS
  Integrative analysis of type-I and type-II aberrations provides an insight into the frequencies, non-random associations and prognostic impact of the various aberrations, reflecting the heterogeneity of pediatric acute myeloid leukemia. These aberrations are likely to guide the stratification of pediatric acute myeloid leukemia and may direct the development of targeted therapies.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Balgobind
authors.forename: Iris H I M
authors.initials: IH
authors.lastname: Hollink
authors.forename: Susan T C J M
authors.initials: ST
authors.lastname: Arentsen-Peters
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Jochen
authors.initials: J
authors.lastname: Harbott
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Anne R M
authors.initials: AR
authors.lastname: von Bergh
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Valerie
authors.initials: V
authors.lastname: de Haas
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zemanova
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Cayuela
authors.forename: Andre
authors.initials: A
authors.lastname: Baruchel
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D015331:Cohort Studies; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D000090243:Nucleophosmin; D011379:Prognosis; D012737:Sex Factors; D016019:Survival Analysis