In particular, inactivation of the Polycomb repressive complex‐2 (PRC2) subunits (e.g., SUZ12 or EED) with resultant loss of H3K27 trimethylation (H3K27me3) has been repeatedly associated with MPNST and with widespread chromosomal instability; concurrent alterations in TP53, CDKN2A and components of the RAS/MAPK and PI3K/AKT/mTOR signaling pathways have also been described, providing a plausible biological route from benign nerve sheath tumors to high‐grade malignancy. This evidence concerns the gene CDKN2A and malignant peripheral nerve sheath tumor.