title: Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.
abstract: Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had ≥1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: T D
authors.initials: TD
authors.lastname: Buitenkamp
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: N E
authors.initials: NE
authors.lastname: Gallimore
authors.forename: A
authors.initials: A
authors.lastname: van der Veer
authors.forename: J P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: H B
authors.initials: HB
authors.lastname: Beverloo
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: V
authors.initials: V
authors.lastname: de Haas
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
authors.forename: A J
authors.initials: AJ
authors.lastname: Vora
authors.forename: C D
authors.initials: CD
authors.lastname: Mitchell
authors.forename: L J
authors.initials: LJ
authors.lastname: Russell
authors.forename: C
authors.initials: C
authors.lastname: Schwab
authors.forename: C J
authors.initials: CJ
authors.lastname: Harrison
authors.forename: A V
authors.initials: AV
authors.lastname: Moorman
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
mesh_terms: D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004314:Down Syndrome / Q000150:complications / Q000235:genetics* / Q000401:mortality; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D015999:Multivariate Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D018121:Receptors, Cytokine / Q000235:genetics*
chemical_list: C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2