Neurofibromatosis Type 1 is caused by heterozygous loss-of function mutations in the NF1 gene, a tumor suppressor gene in the RAS molecular pathway. The condition is a tumor predisposition syndrome, affecting about 1 in 3,000 people. The tumors formed in NF1 arise through somatic loss of teh second allele, although this has not been proven in all cases. About 50% of people with NF1 have one or more plexiform neurofibromas, most of which are internal and not suspected clinically. Plexiform neurofibromas are not malignant, but can cause disfigurement and may compromise neurological function or even jeopardize life. For example, they may erode bone in the vertebral column and lead to spinal cord injury, or they may involve the airway.
There is a need for effective treatments to shrink plexiform neurofibromas. Surgical treatment of plexiform neurofibromas is often unsatisfactory, as it is not possible to achieve complete resection, and the tumors involve vital nerves and blood vessels. Medical treatments have been largely ineffective with the more recent exception of MEK inhibitors which act on the RAS pathway. Notably, many other modifiers of the RAS pathway have been tried.
Plexiform neurofibromas may acquire additional mutations over time, and become malignant peripheral nerve sheath tumors. Complete surgical excision of malignant peripheral nerve sheath tumors. Complete surgical excision of MPNTs is the only effective treatment, but the tumors have often metastasized by the time they are detected, and outcomes are poor. The lifetime risk of and MPNST evolving from a plexiform neurofibroma is 8-13% (Evans, 2002).
Understanding the molecular evolution of both types could help identify more effective medical treatments. In addition, understanding the molecular evolution of MPNST could form the basis of a highly sensitive "liquid biopsy" for this tumor type.
Evans, D. G. R. (2002). Malignant peripheral nerve sheath tumours in neurofibromatosis 1. Journal of Medical Genetics, 39(5), 311–314. http://doi.org/10.1136/jmg.39.5.311
Hirbe, A., Dahiya, S. M., Miller, C., Li, T., Fulton, R., Zhang, X., … Gutmann, D. H. (2015). Whole exome sequencing reveals the order of genetic changes during malignant transformation and metastasis in a single patient with NF1-plexiform neurofibroma. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. http://doi.org/10.1158/1078-0432.CCR-14-3049
Lee, W., Teckie, S., Wiesner, T., Ran, L., Prieto Granada, C. N., Lin, M., … Chi, P. (2014). PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nature Genetics, 46(11), 1227–32. http://doi.org/10.1038/ng.3095
McPherson, J. R., Ong, C.-K., Ng, C. C.-Y., Rajasegaran, V., Heng, H.-L., Yu, W. S.-S., … Yap, Y.-S. (2015). Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1. Cancer Medicine, 4(12), 1871–1878. http://doi.org/10.1002/cam4.551
Patel, A. V, Chaney, K. E., Choi, K., Largaespada, D. A., Kumar, A. R., & Ratner, N. (2016). An ShRNA Screen Identifies MEIS1 as a Driver of Malignant Peripheral Nerve Sheath Tumors ☆. EBIOM, 9, 110–119. http://doi.org/10.1016/j.ebiom.2016.06.007
Rahrmann, E. P., Watson, A. L., Keng, V. W., Choi, K., Moriarity, B. S., Beckmann, D. A., … Largaespada, D. A. (2013). Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nature Genetics, 45(7), 756–66. http://doi.org/10.1038/ng.2641
Röhrich, M., Koelsche, C., Schrimpf, D., Capper, D., Sahm, F., Kratz, A., … Reuss, D. E. (2016). Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathologica, 131(6), 877–887. http://doi.org/10.1007/s00401-016-1540-6
Subramanian, S., Thayanithy, V., West, R. B., Lee, C.-H., Beck, A. H., Zhu, S., … van de Rijn, M. (2010). Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours. The Journal of Pathology, 220(1), 58–70. http://doi.org/10.1002/path.2633
Thway, K., & Fisher, C. (2014). Malignant peripheral nerve sheath tumor: pathology and genetics. Annals of Diagnostic Pathology, 18(2), 109–16. http://doi.org/10.1016/j.anndiagpath.2013.10.007
Zhang, M., Wang, Y., Jones, S., Sausen, M., McMahon, K., Sharma, R., … Bettegowda, C. (2014). Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nature Genetics, 46(11), 1170–1172. http://doi.org/10.1038/ng.3116