Integrated Epigenetic and Transcriptomic Analysis Identifies Interleukin 17 DNA Methylation Signature of Malignant Peripheral Nerve Sheath Tumor Progression and Metastasis

Abstract

PURPOSE Sarcomas are a complex group of highly aggressive and metastatic tumors with over 100 distinct subtypes. Because of their diversity and rarity, it is challenging to generate multisarcoma signatures that are predictive of patient outcomes. MATERIALS AND METHODS Here, we identify a DNA methylation signature for progression and metastasis of numerous sarcoma subtypes using multiple epigenetic and genomic patient data sets. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly metastatic sarcomas with frequent loss of the histone methyltransferase, PRC2. Loss of PRC2 is associated with MPNST metastasis and plays a critical noncanonical role in DNA methylation. RESULTS We found that over 900 5′—C—phosphate—G—3′ (CpGs) were hypermethylated in MPNSTs with PRC2 loss. Furthermore, we identified eight differentially methylated CpGs in the IL17D/ RD family that correlate with the progression and metastasis of MPNSTs in two independent patient data sets. Similar trends were identified in other sarcoma subtypes, including osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. Analysis of scRNAseq data sets determined that IL17D/ RD expression occurs in both the tumor cells and the surrounding stromal populations. CONCLUSION These results might have broad implications for the clinical management and surveillance of sarcoma.