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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5951-5960.
Prepublished online as a Blood First Edition Paper on January 26, 2009; DOI 10.1182/blood-2008-09-177949.
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Submitted September 8, 2008
Accepted January 7, 2009
Clinical relevance of Wilms' tumor 1 gene mutations in childhood acute myeloid leukemia
Iris H.I.M. Hollink, Marry M. van den Heuvel-Eibrink, Martin Zimmermann, Brian V. Balgobind, Susan T.C.J.M. Arentsen-Peters, Marielle Alders, Andre Willasch, Gertjan J.L. Kaspers, Jan Trka, Andre Baruchel, Siebold S.N. de Graaf, Ursula Creutzig, Rob Pieters, Dirk Reinhardt, and C. Michel Zwaan*
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
AML-BFM Study Group, Department of Pediatric Oncology/Hematology, Medical High School, Hannover, Germany
Clinical Genetics, Academic Medical Center, Amsterdam, Netherlands
Department of Hematology and Oncology, University Children's Hospital of Frankfurt, Frankfurt, Germany
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands
Pediatric Haematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic
Hematology, Saint-Louis Hospital, Paris, France
Department of Pediatric Oncology/Hematology, Radboud University Medical Center, Nijmegen, Netherlands
AML-BFM Study Group, University Children's Hospital, Munster, Germany
* Corresponding author; email: c.m.zwaan{at}erasmusmc.nl.
WT1 mutations have recently been identified in ~10% of adult AML with normal cytogenetics (CN-AML), and are associated with poor outcome. Using array-CGH 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 35/298(12%) diagnostic pediatric AML samples. In 19/35(54%) samples more than one WT1 aberration was found, i.e. two different mutations (n=15), a homozygous mutation (n=2), or a mutation plus a WT1-deletion (n=2). WT1 mutations clustered significantly in the CN-AML subgroup (22%; p<0.001), and were associated with FLT3/ITD (43% vs. 17%; p<0.001). WT1 mutations conferred an independent poor prognostic significance (WT1-mutated vs. wild-type patients: 5-year pOS 35% vs. 66%, p=0.002; pEFS 22% vs. 46%, p<0.001; and CIR 70% vs. 44%, p<0.001, respectively). Patients with both a WT1 mutation and a FLT3/ITD had a dismal prognosis (5-years pOS 21%). In 4/28(14%) paired diagnosis-relapse samples, a WT1 mutation was gained at relapse; moreover, all WT1-mutated diagnostic samples (n=11) presented the same mutation at relapse. In conclusion, WT1 mutations occur at a significant rate in childhood AML, and are a novel independent poor prognostic marker.
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