title: Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia.
abstract: Wilms tumor 1 (WT1) mutations have recently been identified in approximately 10% of adult acute myeloid leukemia (AML) with normal cytogenetics (CN-AML) and are associated with poor outcome. Using array-based comparative genome hybridization in pediatric CN-AML samples, we detected a WT1 deletion in one sample. The other WT1 allele was mutated. This prompted us to further investigate the role of WT1 aberrations in childhood AML. Mutations were found in 35 of 298 (12%) diagnostic pediatric AML samples. In 19 of 35 (54%) samples, more than one WT1 aberration was found: 15 samples had 2 different mutations, 2 had a homozygous mutation, and 2 had a mutation plus a WT1 deletion. WT1 mutations clustered significantly in the CN-AML subgroup (22%; P < .001) and were associated with FLT3/ITD (43 vs 17%; P < .001). WT1 mutations conferred an independent poor prognostic significance (WT1 mutated vs wild-type patients: 5-year probability of overall survival [pOS] 35% vs 66%, P = .002; probability of event-free survival 22% vs 46%, P < .001; and cumulative incidence of relapse or regression 70% vs 44%, P < .001). Patients with both a WT1 mutation and a FLT3/ITD had a dismal prognosis (5-year pOS 21%). WT1 mutations occur at a significant rate in childhood AML and are a novel independent poor prognostic marker.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Iris H I M
authors.initials: IH
authors.lastname: Hollink
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Brian V
authors.initials: BV
authors.lastname: Balgobind
authors.forename: Susan T C J M
authors.initials: ST
authors.lastname: Arentsen-Peters
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.forename: Andre
authors.initials: A
authors.lastname: Willasch
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.forename: Andre
authors.initials: A
authors.lastname: Baruchel
authors.forename: Siebold S N
authors.initials: SS
authors.lastname: de Graaf
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D012008:Recurrence; D015996:Survival Rate; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025721:WT1 Proteins