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Identification of novel NOTCH1 mutations: Increasing our knowledge of the NOTCH signaling pathway
Author(s) -
Gallo Llorente L.,
Luther H.,
Schneppenheim R.,
Zimmermann M.,
Felice M.,
Horstmann M.A.
Publication year - 2014
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.24852
Subject(s) - mutation , phenotype , notch signaling pathway , medicine , ankyrin repeat , genetics , cohort , ankyrin , gene , cancer research , biology
Background Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T‐ALL, but its impact on prognosis remains unclear. Procedure We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC‐BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long‐term outcome. Results Overall, 101 out of 165 (61.2%) T‐ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations. Eight T‐ALL samples (4.8%) exclusively revealed FBXW7 mutations. Fifty‐six T‐ALL (33.9%) exhibited a wild‐type configuration of either gene. Four novel NOTCH1 mutations were identified localized in the C‐terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain. Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss‐of‐function mutation. Conclusions Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T‐ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy ( P = 0.009). Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications. Pediatr Blood Cancer 2014;61:788–796. © 2013 Wiley Periodicals, Inc.