Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. The N-terminal tail of histone H3 can undergo several different types of epigenetic modifications that influence cellular processes. These modifications include the covalent attachment of methyl or acetyl groups to lysine and arginine amino acids and the phosphorylation of serine or threonine. Loss-of-function somatic alterations in different components of the polycomb repressive complex 2 (PRC2) occur in the majority of malignant peripheral nerve sheath tumors (MPNSTs). These highly recurrent and specific inactivation of PRC2 components co-occurred with somatic alterations of CDKN2A and NF1. MPNSTs with PCR2 inactivation through EED or SUZ12 alterations showed consistent complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) by IHC analysis. Approximately 90% of sporadic and radiation associated MPNSTs and 50% NF1-associated MPNSTs show loss of H3K27me3 expression.