Abstract 6011: Methylation profiling reveals the role of PRC2 in regulating DNA methylome changes in malignant peripheral nerve sheath tumors

Abstract

Abstract Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer predisposition syndrome defined by germline deletion of one NF1 allele. Somatic loss of heterozygosity in the remaining NF1 allele in Schwann lineage cells gives rise to benign tumors known as plexiform neurofibromas. These tumors have a high risk of developing into cancerous lesions known as malignant peripheral nerve sheath tumors (MPNST) through the sequential deletion of CDKN2A/B followed by recurrent mutations in SUZ12 or EED, constituting the inactivation of polycomb repressor complex 2 (PRC2). PRC2 is a transcriptional repressor complex involved in the silencing of several genes throughout cell development and differentiation. Loss of this complex leads to a depletion in trimethylation marks on Histone H3 Lysine 27 (H3K27me3) and the subsequent gain of acetylation marks on the same lysine residue (H3K27Ac). However, full range of epigenetic consequences of these events are currently not well characterized, especially with respect to MPNST formation and development. The Largaespada lab has developed Schwann cell lines engineered to harbor deletions in NF1 and either SUZ12 or EED and assayed the methylation status of 850,000 CpG sites using the EPIC array. The resulting methylation profiles reveal a large degree of change in promoter methylation between cell lines with and without PRC2 inactivation. These changes, however, appear to be inconsistent. To further understand this phenomenon, I have analyzed differential methylation patterns between lines with SUZ12/EED deletions on top of NF1 deletion compared to those with NF1 deletion alone. Pathway analysis of genes whose promoters are differentially methylated upon PRC2 reveals a bias towards developmental modules such as morphogenesis and neuronal differentiation, suggesting that DNA methylation is a mechanism by which PRC2 loss promotes stemness in Schwann lineage cells prior to MPNST formation. Additionally, differentially methylated regions were overlapped with functional non-coding elements in the genome to understand potential ripple effects in the epigenome. These findings underline the importance of DNA methylation in contributing to tumor formation and define unique functions by which PRC2 specifically leverages diverse methylation states to drive malignant transformation in Schwann lineage cells. Citation Format: Christopher M. Stehn, Minu Bhunia, Kyle B. Williams, Alex T. Larsson, David A. Largaespada. Methylation profiling reveals the role of PRC2 in regulating DNA methylome changes in malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6011.