Key Points
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The neurofibromatosis type 1 (NF1) research community has identified the NF1 gene and has developed mouse models of plexiform neurofibroma, optic pathway glioma, malignant peripheral nerve sheath tumours and juvenile myelomonocytic leukaemia, all of which are tumours that are found in patients with NF1.
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The NF1 gene encodes a RAS GTPase-activating protein known as neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies.
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Preclinical and clinical testing consortia have found that inhibition of MEK shrinks benign tumours but that combinatorial therapies are likely to be needed for NF1-related malignancies. These may include targeting of other RAS effector pathways. Treatments that target NF1 could also be tested as treatments for other RASopathies.
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The neurofibromin protein has been studied, and many potential interacting partners have been identified. However, many questions remain concerning the functional importance of possible interaction partners and roles of neurofibromin protein domains, and the interactions between neurofibromin and cyclic AMP signalling pathways.
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NF1 mutations are common in most sporadic tumour types and can mediate resistance to therapy.
Abstract
Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.
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Acknowledgements
The authors apologize to colleagues whose work they were unable to cite owing to space limitations or inadvertent omission. They have attempted to emphasize remaining questions and the most recent data in the field. They thank K. M. Cichowski (Brigham and Women's Hospital, Massachusetts, USA), E. Schorry and N. Nassar (Cincinnati Children's Hospital, Ohio, USA), and B. Widemann (US National Cancer Institute) for reviewing the draft manuscript. N.R. is supported by grants from the US National Institutes of Health, the Department of Defense Program on Neurofibromatosis, the Children's Tumor Foundation and the Neurofibromatosis Therapeutic Acceleration Programs.
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Glossary
- Café-au-lait macules
-
Hyperpigmented spots on the skin of patients with neurofibromatosis type 1 (NF1). They are used as an NF1 diagnostic criterion, particularly in young children.
- Polycomb repressive complex 2
-
A complex that regulates epigenetic silencing of chromatin and includes the subunits SUZ12, EED, EZH1 or EZH2 and RBAP48. It also has histone methyltransferase activity.
- Astrocytes
-
The most abundant type of glial cell in the central nervous system. Astrocytes regulate the extracellular neuronal environment.
- Imprinting control region
-
A regulatory element (a segment of DNA) that is modified by methylation to regulate gene expression.
- Schwann cells
-
Glial cells derived from neural crest cells that ensheathe and myelinate axons in the peripheral nervous system.
- Oligodendrocytes
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Glial cells derived from neuroepithelial cells that ensheathe and myelinate axons in the central nervous system.
- NG2 cells
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Oligodendrocyte progenitor cells that may have additional functions in the mature brain.
- Aurora kinase
-
A serine/threonine kinase that functions during mitosis and is required for correct function of centrosomes.
- Bromodomain inhibitors
-
A new class of epigenetic modulators of gene expression.
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Ratner, N., Miller, S. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15, 290–301 (2015). https://doi.org/10.1038/nrc3911
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DOI: https://doi.org/10.1038/nrc3911
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