title: IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  To determine the prevalence and prognostic impact of significant acute lymphoblastic leukemia (ALL) -related genes: CRLF2 deregulation (CRLF2-d), IGH@ translocations (IGH@-t), and deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, and EBF1 in adolescents and adults.
  
  
  METHODS
  The cohort comprised 454 patients (age 15 to 60 years old) treated on the multicenter United Kingdom Acute Lymphoblastic Leukaemia Trial XII/Eastern Cooperative Oncology Group 2993 trial (UKALLXII/ECOG2993) with Philadelphia-negative B-cell precursor ALL. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used to detect these genetic alterations.
  
  
  RESULTS
  Twenty patients (5%) had CRLF2-d (P2RY8-CRLF2, n = 7; IGH@-CRLF2, n = 13), and 36 patients (8%) harbored an IGH@-t with a different partner gene. There was little overlap between IGH@-t, CRLF2-d, and established chromosomal abnormalities. Deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, or EBF1 were prevalent with 101 (33%) of 304 patients harboring one and 102 (33%) harboring two or more alterations, occurring with varying frequency in all cytogenetic subgroups. The 5-year event-free survival, relapse-free survival (RFS), and overall survival (OS) rates for the whole cohort were 40%, 55%, and 43%, respectively. Patients with CRLF2-d, IGH@-t, and IKZF1 deletions were associated with an inferior outcome in univariate but not multivariate analysis. In particular, CRLF2-d patients had a lower RFS compared with other patients (30%), whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%, respectively).
  
  
  CONCLUSIONS
  CRLF2-d and IGH@-t represent distinct subtypes of adolescent and adult ALL. Deletions of key B-cell differentiation and cell cycle control genes are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d, IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and adult ALL.
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Level 5, Sir James Spence Institute, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle-upon-Tyne, NE1 4LP, United Kingdom. anthony.moorman@ncl.ac.uk
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Ensor
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Russell
authors.forename: Heather
authors.initials: H
authors.lastname: Morrison
authors.forename: Lisa
authors.initials: L
authors.lastname: Jones
authors.forename: Dino
authors.initials: D
authors.lastname: Masic
authors.forename: Bella
authors.initials: B
authors.lastname: Patel
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Martin
authors.initials: M
authors.lastname: Tallman
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Goldstone
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D016009:Chi-Square Distribution; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D015999:Multivariate Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016016:Proportional Hazards Models; D018121:Receptors, Cytokine / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult
chemical_list: C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D007143:Immunoglobulin Heavy Chains; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor