Comparative study of human and canine nerve sheath tumors in terms of morphology, prognosis, treatment, epigenetics, transcriptomics, and genomics

INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas. An obstacle to treating MPNSTs is a lack of effective systemic therapies. Although over 70% of human MPNSTs have lost or inactivated the epigenome regulator polycomb repressive complex 2 ( PRC2 ) (DeRaedt et al. , Nature , 2014), its activity and contribution to canine PNST progression remain unclear. METHODS: This study compared canine peripheral nerve sheath tumors (PNSTs) and human MPNSTs across biological and clinical features, including PRC2 activity. Immunohistochemical analysis was performed for a human tissue microarray of 54 neurofibromas and 139 MPNSTs, and 63 canine PNSTs for H3K27me3, a repressive histone mark deposited by intact PRC2, and H3K27ac, which increases globally upon H3K27me3 loss. To understand the genomic alterations present in canine PNSTs, we analyzed tumor mutation burden, copy number alteration, and transcriptomes of eight canine PNST/normal pairs. RESULTS: The results suggested that H3K27me3 loss and associated gain of H3K27ac epigenetically drive human and canine tumors. This study provided evidence that human and canine PNSTs are clinicopathologically similar and may also be similarly driven by epigenetic mechanisms. CONCLUSIONS: Further studies are warranted to evaluate whether these epigenetic deregulations alter similar gene signatures in humans and canine patients. The knowledge gained from this work advances our understanding of the molecular drivers of MPNST and informs potential therapeutics to evaluate in future clinical studies.