Genomic landscape of superficial malignant peripheral nerve sheath tumor.

Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers and can be difficult to distinguish from spindle cell (SCM) or desmoplastic (DM) melanomas. Their biology is poorly understood. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on SF-MPNST (n=8) and compared these to cases of SCM (n=7), DM (n=8), and deep MPNST (D-MPNST, n=8). Immunohistochemical staining for H3K27me3 and PRAME was also performed. SF-MPNST demonstrated intermediate features between D-MPNST and melanoma. Patients were younger than those with melanoma, and older than those with D-MPNST; outcome was worse and better respectively. SF-MPNST tumor mutational burden (TMB) was higher than D-MPNST and lower than melanoma; differences were significant only between SF-MPNST and SCM (p = 0.0454) and between D-MPNST and SCM (p = 0.001, Dunn's Kruskal-Wallis post-hoc test). Despite having an overlapping mutational profile in some common cancer-associated genes, the COSMIC mutational signatures clustered DM and SCM together with ultraviolet light exposure signatures (SBS7a, 7b), and SF- and D-MPNST together with defective DNA base excision repair (SBS30, 36). RNA-seq revealed differentially expressed genes between SF-MPNST and SCM (1670 genes), DM (831 genes), and D-MPNST (614 genes), some of which hold promise for development as immunohistochemical markers (SOX8, PLCH1) or aids (MLPH, CALB2, SOX11, TBX4). H3K27me3 immunoreactivity was diffusely lost in most D-MPNSTs (7/8, 88%), but showed variable and patchy loss in SF-MPNSTs (2/8, 25%). PRAME was entirely negative in the majority (0+ in 20/31, 65%), including 11/15 melanomas, and showed no significant difference between groups (p=0.105, Kruskal-Wallis test). Expression of immune cell transcripts was upregulated in melanomas relative to MPNSTs. Next-generation sequencing revealed multiple differential features between SF- MPNST, D-MPNST, SCM, and DM, including tumor mutation burden, mutational signatures, and differentially expressed genes. These findings help advance our understanding of disease pathogenesis and improve diagnostic modalities.