The NF1 gene revisited - from bench to bedside

Abstract

Neurofibromatosis type 1 (NF1) is a relatively common tumour predisposition syndrome related to germline aberrations of NF1, a tumour suppressor gene. The gene product neurofibromin is a negative regulator of the Ras cellular proliferation pathway, and also exerts tumour suppression via other mechanisms.Recent next-generation sequencing projects have revealed somatic NF1 aberrations in various sporadic tumours. NF1 plays a critical role in a wide range of tumours. NF1 alterations appear to be associated with resistance to therapy and adverse outcomes in several tumour types.Identification of a patient's germline or somatic NF1 aberrations can be challenging, as NF1 is one of the largest human genes, with a myriad of possible mutations. Epigenetic factors may also contribute to inadequate levels of neurofibromin in cancer cells.Clinical trials of NF1-based therapeutic approaches are currently limited. Preclinical studies on neurofibromin-deficient malignancies have mainly been on malignant peripheral nerve sheath tumour cell lines or xenografts derived from NF1 patients. However, the emerging recognition of the role of NF1 in sporadic cancers may lead to the development of NF1-based treatments for other tumour types. Improved understanding of the implications of NF1 aberrations is critical for the development of novel therapeutic strategies.

Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets

“…NF1 encodes neurofibromin, which functions as a tumour suppressor via inactivation of RAS oncogene that serves to downregulate mitogen-activated protein kinase and the PI3K/AKT/mTOR pathway. Somatic NF1 alterations have been reported in various sporadic tumours including glioblastoma, melanoma, cancers of ovary, breast and lung, hematolymphoid malignancy and sarcoma 42. Data on NF1 in cholangiocarcinoma are limited; 1 of 28 IHCCA was found to harbour somatic NF1 mutation using an NGS-based platform 32…”

NF1 Mutations Are Common in Desmoplastic Melanoma

“…Prior studies on the mutation profile of melanomas reported a frequency of NF1 mutations in 16 of 121 (13%) tumors 29 , and in 13 of 91 (14%) 30 , respectively. In a recent review the overall frequency of NF1 mutations was estimated at 14% of cutaneous melanomas, with a total of 475 specimens analyzed 31 . No information was provided about the histopathologic subtype, but it is unlikely that a significant number of DM was included in those studies, because DM is a rare variant of melanoma (approximately 4 % of primary melanomas) 3, 32 .…”

Next-generation molecular therapy in lung cancer

“…NF1 is 1 of 6 genes significantly mutated in both subtypes, implying a potential driver pathway that warrants further study in both subtypes. Nonetheless, the number clinical trials of NF1-based therapeutic approaches are currently limited (8). Improved understanding of the implications of NF1 aberrations is critical for the development of novel therapeutic strategies.…”