title: CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol.
abstract: DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728.
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium Center for Medical Genetics, Ghent University Hospital, Belgium.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Ghazavi
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France Hematology University Institute, University Paris-Diderot, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Lammens
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France Hematology University Institute, University Paris-Diderot, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caye
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Zegrari
authors.affiliation: Department of Hematology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Bakkus
authors.affiliation: Centre de Biologie Pathologie PM Degand, INSERM U837, Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grardel
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Institute of Hematology and Oncology Paediatrics, Hospices Civils de Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: Department of Hematology, CHRU, Caen, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Minckes
authors.affiliation: Department of Pediatrics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Vitor
authors.initials: V
authors.lastname: Costa
authors.affiliation: Department of Hemato-Oncology, HUDERF, Brussels, Belgium.
authors.forename: Alina
authors.initials: A
authors.lastname: Ferster
authors.affiliation: Department of Pediatric Hematology-Oncology, CHR, Lille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Mazingue
authors.affiliation: Department of Hematology, Children's Hospital, Toulouse, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Plat
authors.affiliation: Department of Hematolo-Oncology, CHRU, Besançon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Plouvier
authors.affiliation: Department of Pediatric Onco-Hematology, Archet University Hospital, Nice, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Poirée
authors.affiliation: Department of Pediatric Hematology-Oncology, University Hospitals Leuven, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Uyttebroeck
authors.affiliation: Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Belgium.
authors.forename: Jutte
authors.initials: J
authors.lastname: van der Werff-Ten Bosch
authors.affiliation: Department of Pediatric Hematology, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Yakouben
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium Center for Medical Genetics, Ghent University Hospital, Belgium.
authors.forename: Hetty
authors.initials: H
authors.lastname: Helsmoortel
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium.
authors.forename: Magali
authors.initials: M
authors.lastname: Meul
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Belgium.
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Philippé
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France Hematology University Institute, University Paris-Diderot, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium barbara.demoerloose@uzgent.be.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
mesh_terms: D000293:Adolescent; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D002986:Clinical Trials as Topic; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011971:Receptors, Immunologic / Q000235:genetics*; D012008:Recurrence
chemical_list: D015703:Antigens, CD; C482586:BTLA protein, human; D011971:Receptors, Immunologic; C042739:antigens, CD200