Molecular targets for NF1-associated malignant peripheral nerve sheath tumor.

Malignant Peripheral Nerve Sheath Tumor (MPNST) is a soft-tissue neurosarcoma. It can occur sporadically, after radiotherapy or in patients with Neurofibromatosis 1 (NF1). The hereditary disorder, NF1, is a common cancer predisposition syndrome. The main genetic feature is the mutation of the NF1 tumor suppressor gene that is inherited in an autosomal dominant, progressive manner. Mutations of the NF1 gene increase the activity of Ras signaling and cause the development of different types of tumors, including subcutaneous and plexiform neurofibromas. These can have further mutations that mediate the transformation into MPNST. Somatic mutations that have been observed are the loss of cell cycle regulators of the CDKN2A gene, and the inactivation of Polycomb Repressive Complex 2 (PRC2), mainly embryonic ectoderm development (EED) or suppressor of zeste 12 homologue (SUZ12). Other molecular pathways that have been targeted for treatment are dual MAPK-mTOR targeting, p53 protein, and MEK-ERK pathway. To advance the therapies focused on delaying or inhibiting malignant tumor formation in NF1, we need to understand the implications of the molecular and genetic pathway that are involved in the transformation into MPNST.