title: Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma.
abstract: OBJECTIVE
  Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/F(mut)), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL.
  
  
  METHODS
  Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/F(mut) were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements.
  
  
  RESULTS
  N/F(mut) were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/F(mut) and identified a poor prognosis group (P = .02). On multivariate analysis of N/F(mut), TCRγ ABD, and FLASH deletion, only N/F(mut) was an independent factor for good prognosis.
  
  
  CONCLUSIONS
  Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.
authors.affiliation: Université Paris Descartes Sorbonne Paris Cite, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Callens
authors.forename: Frederic
authors.initials: F
authors.lastname: Baleydier
authors.forename: Etienne
authors.initials: E
authors.lastname: Lengline
authors.forename: Raouf
authors.initials: R
authors.lastname: Ben Abdelali
authors.forename: Arnaud
authors.initials: A
authors.lastname: Petit
authors.forename: Patrick
authors.initials: P
authors.lastname: Villarese
authors.forename: Agata
authors.initials: A
authors.lastname: Cieslak
authors.forename: Veronique
authors.initials: V
authors.lastname: Minard-Colin
authors.forename: Anne
authors.initials: A
authors.lastname: Rullier
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: Claudine
authors.initials: C
authors.lastname: Schmitt
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
mesh_terms: D000293:Adolescent; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C485604:CASP8AP2 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D044767:Ubiquitin-Protein Ligases