title: A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
abstract: BACKGROUND
  Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children.
  
  
  METHODS
  We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics.
  
  
  RESULTS
  Our classifier predicted ALL subtype with a median accuracy of 90.0% (IQR 88.3-91.7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87.9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR-ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR-ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59.5%, 95% CI 37.1-81.9) compared with patients with other precursor B-ALL (84.4%, 76.8-92.1%; p=0.012), a prognosis similar to that of patients with BCR-ABL1-positive ALL (51.9%, 23.1-80.6%). In the DCOG cohort, the prognosis of BCR-ABL1-like disease (57.1%, 31.2-83.1%) was worse than that of other precursor B-ALL (79.2%, 70.2-88.3%; p=0.026), and similar to that of BCR-ABL1-positive ALL (32.5%, 2.3-62.7%). 36 (82%) of the patients with BCR-ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0.0002). Compared with other precursor B-ALL cells, BCR-ABL1-like cells were 73 times more resistant to L-asparaginase (p=0.001) and 1.6 times more resistant to daunorubicin (p=0.017), but toxicity of prednisolone and vincristine did not differ.
  
  
  CONCLUSIONS
  New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL.
  
  
  BACKGROUND
  Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.
authors.affiliation: Department of Paediatric Oncology and Haematology, Erasmus MC-Sophia Children's Hospital, University Medical Centre, Rotterdam, Netherlands. m.l.denboer@erasmusmc.nl
authors.forename: Monique L
authors.initials: ML
authors.lastname: Den Boer
authors.forename: Marjon
authors.initials: M
authors.lastname: van Slegtenhorst
authors.forename: Renée X
authors.initials: RX
authors.lastname: De Menezes
authors.forename: Meyling H
authors.initials: MH
authors.lastname: Cheok
authors.forename: Jessica G C A M
authors.initials: JG
authors.lastname: Buijs-Gladdines
authors.forename: Susan T C J M
authors.initials: ST
authors.lastname: Peters
authors.forename: Laura J C M
authors.initials: LJ
authors.lastname: Van Zutven
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van der Spek
authors.forename: Gaby
authors.initials: G
authors.lastname: Escherich
authors.forename: Martin A
authors.initials: MA
authors.lastname: Horstmann
authors.forename: Gritta E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: Willem A
authors.initials: WA
authors.lastname: Kamps
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
mesh_terms: D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D015870:Gene Expression; D020869:Gene Expression Profiling; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D016896:Treatment Outcome