Although the model has been largely elucidated by numerous studies highlighting key events such as (i) biallelic inactivation of NF1, as a common prerequisite; (ii) involvement of TP53; (iii) loss of function of PRC2 complex by mutations/deletions of SUZ12 and EED, associated with global loss of H3K27me3; and (iv) progressive genomic complexification with large somatic CNVs in advanced stages, the precise molecular mechanisms determining the transformation of the PN, which is histologically classified as a benign tumor, are still largely unknown in MPNST. This evidence concerns the gene NF1 and malignant peripheral nerve sheath tumor.