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 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.
Highlights
Neurofibromatosis type 1, known as NF1 or von Recklinghausen’s disease, is a tumour predisposition syndrome characterized by the development of multiple neurofibromas, café-au-lait spots and Lisch nodules
In keeping with the observation that NF1 individuals are at increased risk of developing phaeochromocytomas, these findings suggest that loss of NF1 function is a crucial event in the pathogenesis of both sporadic and NF1-associated phaeochromocytomas [91, 141, 142]
There is preclinical data to support the activity of MEK inhibitors, Ras inhibitor farnesylthiosalicylic acid, sirolimus, everolimus and PI3K/Akt/mTOR inhibitors in malignant peripheral nerve sheath tumour (MPNST) cell lines or xenografts derived from NF1 patients [163, 170,171,172,173,174] (Figure 3)
Summary
Neurofibromatosis type 1, known as NF1 or von Recklinghausen’s disease, is a tumour predisposition syndrome characterized by the development of multiple neurofibromas, café-au-lait spots and Lisch nodules.Initially described by Professor Von Recklinghausen, a German pathologist back in 1882, NF1 is one of the most common genetic disorders worldwide [1, 2]. Preclinical studies on neurofibromin-deficient malignancies have mainly been on malignant peripheral nerve sheath tumour cell lines or xenografts derived from NF1 patients.
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