title: Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study.
abstract: Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van der Veer
authors.affiliation: Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Rizopoulos
authors.affiliation: DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands.|Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Fiocco
authors.affiliation: DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Sonneveld
authors.affiliation: DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands.
authors.forename: H A
authors.initials: HA
authors.lastname: de Groot-Kruseman
authors.affiliation: Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Kuiper
authors.affiliation: DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands.|Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Hoogerbrugge
authors.affiliation: COALL Study Group, Research Centre and Clinic for Pediatric Oncology, University Medical Centre Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Horstmann
authors.affiliation: BFM-G, Berlin-Frankfurt-Münster-Germany Study Group, University of Schleswig-Holstein, Kiel, Germany.|CLIP, Childhood Leukaemia Investigation Prague, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Zaliova
authors.affiliation: AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica, University of Milano-Bicocca, Monza, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Palmi
authors.affiliation: CLIP, Childhood Leukaemia Investigation Prague, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Trka
authors.affiliation: CLIP, Childhood Leukaemia Investigation Prague, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: E
authors.initials: E
authors.lastname: Fronkova
authors.affiliation: Pediatric Haematology and Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Emerenciano
authors.affiliation: Pediatric Haematology and Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: do Socorro Pombo-de-Oliveira
authors.affiliation: PPLLSG, Polish Pediatric Leukaemia Lymphoma Study Group, Department of Pediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Mlynarski
authors.affiliation: PPLLSG, Polish Pediatric Leukaemia Lymphoma Study Group, Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Szczepanski
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Nebral
authors.affiliation: BFM-A, Berlin-Frankfurt-Münster-Austria Study Group, Department of Pediatric Hematology and Oncology, St Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Attarbaschi
authors.affiliation: ANZCHOG, Australian and New Zealand Children's Oncology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Venn
authors.affiliation: ANZCHOG, Australian and New Zealand Children's Oncology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: R
authors.identifier: http://orcid.org/0000-0002-0188-6005
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Schwab
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Enshaei
authors.affiliation: Department of Haematology, Sheffield Children's Hospital, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Vora
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: BFM-G, Berlin-Frankfurt-Münster-Germany Study Group, University of Schleswig-Holstein, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica, University of Milano-Bicocca, Monza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica, University of Milano-Bicocca, Monza, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Conter
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.|DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands.|Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.|DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000032:analysis; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D007391:International Cooperation; D015514:Oncogene Proteins, Fusion / Q000032:analysis; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D051740:Ikaros Transcription Factor; D015514:Oncogene Proteins, Fusion; C497239:IKZF1 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein