title: Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol.
abstract: OBJECTIVE
  Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.
  
  
  METHODS
  NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome.
  
  
  RESULTS
  NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72).
  
  
  CONCLUSIONS
  NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.
authors.affiliation: Department of Haematology, University College London, UCL Cancer Institute, WC1E 6BT, United Kingdom. m.mansour@ucl.ac.uk
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.forename: Maria L
authors.initials: ML
authors.lastname: Sulis
authors.forename: Veronique
authors.initials: V
authors.lastname: Duke
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: Sarah
authors.initials: S
authors.lastname: Jenkinson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Koo
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Allen
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: Georgina
authors.initials: G
authors.lastname: Buck
authors.forename: Sue
authors.initials: S
authors.lastname: Richards
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Goldstone
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000628:therapy*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases