Evolution of Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1: Opportunities for Prevention and Therapeutic Strategies

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of 1:3,000. Pathogenic germline variants in the NF1 gene result in loss of the NF1 gene product, neurofibromin, which leads to hyperactivation of the RAS and other signaling pathways and tumorigenesis. A hallmark feature of NF1 is the development of peripheral nerve sheath tumors (PNSTs) ranging from histologically benign plexiform neurofibromas (PNs) to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), which lack effective medical therapies. Preclinical–clinical collaborations have led to substantial progress in the understanding of the biology and natural history of PNSTs. This has resulted in regulatory approvals of a targeted therapy, MEK inhibitors, for NF1 PNs. In addition, genomic studies and the development of liquid biomarkers have elucidated the evolution of PNs to MPNSTs, offering opportunities for earlier diagnosis and the development of prevention and therapeutic strategies.