Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia.
BACKGROUND
Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether NOTCH1 mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases.


METHODS
T-ALL subtypes, status of SIL-TAL1 fusion, ectopic expression of TLX3, and mutations in FBXW7, KRAS, PTEN and NOTCH1 were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test.


RESULTS
The frequencies of mutations were 43.5% for NOTCH1, while FBXW7, KRAS and PTEN exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of NOTCH1 mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between NOTCH1 mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. SIL-TAL1 was identified as an adverse prognostic factor. NOTCH1 mutation status was not associated with outcome, while the presence of NOTCH1 complex mutations (indels) were associated with a longer overall survival (p = 0.031) than point mutations.


CONCLUSIONS
NOTCH1 mutations alone or in combination with FBXW7 did not impact T-ALL prognosis. Nevertheless, complex NOTCH1 mutations appear to have a positive impact on OS and the SIL-TAL1 fusion was validated as a negative prognostic marker in our series of T-ALL.
Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
Marcela Braga
MB
Mansur
Rocio
R
Hassan
Thayana C
TC
Barbosa
Alessandra
A
Splendore
Patricia Y
PY
Jotta
José Andrés
JA
Yunes
Joseph L
JL
Wiemels
Maria S
MS
Pombo-de-Oliveira
D000293:Adolescent; 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; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000401:mortality*; D008297:Male; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051881:Receptor, Notch1 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D018398:Homeodomain Proteins; C117307:KRAS protein, human; C497761:NOTCH1 protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; C547584:SIL-TAL1 fusion protein, human; C489494:TLX3 protein, human; D044767:Ubiquitin-Protein Ligases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins