Abstract 843: Epigenomic disruption of adipogenic regulators in dedifferentiated liposarcoma

Abstract

Abstract Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) are the most common soft-tissue sarcomas in adults. They develop as a result of a disturbance in adipogenic differentiation however, the epigenomic changes underlying liposarcomagenesis are unknown. Here, we aimed to elucidate the role of epigenomic alterations in the initiation of DDLPS. Genome-wide DNA methylation profiles of 15 liposarcoma (6 WDLPS and 9 DDLPS) samples and 6 normal adipose tissue samples were obtained using the Infinium MethylationEPIC BeadChip. After grouping neighboring probes into genomic blocks (GBs, < 500 bp), principal component analysis of all the CpG GBs (n = 535,684) was conducted. Each of normal adipose tissue and WDLPS grouped closely while DDLPS distributed broadly, indicating heterogeneous methylation profiles among the DDLPS samples. Unsupervised hierarchical cluster analysis of enhancers (2,000 GBs with the high SD of 23,478 GBs) classified the samples into three tissue types, whereas that of promoters (1,000 GBs with the high SD of 8,668 GBs) could not classify the DDLPS samples distinctly. The Jonckheere-Terpstra trend test revealed 9,945 hypermethylated (p < 0.01, Δβ > 0.2) GBs in DDLPS compared to those in normal adipose tissues and WDLPS samples. Based upon a report on enhancers in adipocytes (Mikkelsen et al. Cell 143, 156-169. 2010), the hypermethylated GBs in DDLPS were enriched with typical- (2.2%: whole genome 1.2%) and super- (13.5%: whole genome 7.0%) enhancers. Genes involved in adipogenesis, including PPARG2, the master regulator of adipogenesis, and its target genes (FABP4 and PLIN1), were aberrantly methylated at the enhancers and repressed in DDLPS. Conversely, promoters were not enriched among hypermethylated GBs in DDLPS (1.2%: whole genome 4.1%). Taken together, these data indicate that aberrant methylation at the enhancers of adipogenic genes might be crucial for the generation of DDLPS. Evaluation of a demethylating agent in combination with a PPARγ agonist as a potential therapeutic is in progress. Citation Format: Hironori Takamatsu, Naoko Hattori, Naofumi Asano, Naoko Iida, Akihiko Yoshida, Eisuke Kobayashi, Robert Nakayama, Morio Matsumoto, Masaya Nakamura, Akira Kawai, Toshikazu Ushijima. Epigenomic disruption of adipogenic regulators in dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 843.