56. Chr8 gain is associated with MPNST transformation

Abstract

Malignant Peripheral Nerve Sheath Tumors, or MPNST, are a rare and aggressive tumor accounting for 4% of all sarcomas that often arise from transformation of a benign precursor tumor (Plexiform Neurofibroma or PN). The majority arise sporadically or in the setting of Neurofibromatosis type 1 (NF1), and when advanced or unresectable, can be difficult to treat effectively. Despite advances in our understanding of MPNST pathobiology, there exist few effective therapeutic options, and clinical trials have not identified any successful investigational agents. Hence, there is a pressing need to better understand the molecular drivers underlying MPNST development and progression. Though our work aimed to better understand the genomic heterogeneity of MPNST, we identified Chr8q gain as a near universal event in MPNST. Chr8q gain was observed in >90% of the cells and was associated with poor overall survival (OS) in soft tissue sarcomas. We found six known cancer drivers residing on Chr8q (RECQL4, SOX17, HEY1, C-MYC, RAD21, and UBR5) that were highly expressed in MPNST, but not benign precursor PN by bulk RNA-seq data. Through CRISPR knockdown experiments, we found that UBR5 is critical for MPNST proliferation and migration. These data suggest that chr8q gain is a critical event in MPNST pathogenesis, at least in part due to expression of UBR5, and may account for the aggressive nature and poor clinical outcomes in this sarcoma subtype.