Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

Abstract

On behalf of the French ALFA groupGermline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small~0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression. Am. J.

Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation?

“…75 The only gene in the minimal deleted region was the tumor suppressor gene NF1 (tumorsuppressor gene neurofibromatosis-1). 75 The relatively high incidence of NF1 deletions in inv (16) AML found in that study still needs to be confirmed, because in other studies, the incidence of NF1 deletions in CBF-AML did not exceed 2% 79,80 and was only 4% in the subset of inv(16) AML. 79 In t(8;21) AML with additional del(9q), the putative tumor suppressor genes TLE1 and TLE4 are regularly deleted.…”

Array comparative genomic hybridization and sequencing of 23 genes in 80 patients with myelofibrosis at chronic or acute phase

“…Several studies have described del(17q) encompassing NF1 tumor suppressor in myeloid malignancies. 45 We identified NF1 deletion in 5 cases and mutations in 2 PMF cases with no CNAs. These cases evolved in AML or the patients died, suggesting that NF1 alterations may contribute to MF progression and poor outcome.…”

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

“…Importantly, sequencing of tumour exomes and genomes has revealed that somatic NF1 mutations are present at incidences from 2.5% to 11.8% in sporadic, predominantly adult, tumour types such as lung cancer 32 , glioblastoma 33 , ovarian cancer 34 , breast cancer 35 and acute myeloid leukaemia (AML) 36 ; however, they are also present in the paediatric tumour rhabdomyosarcoma.…”