Abstract 5686: Integrative Genomic Analysis Reveals Hypermethylation Triggered GPER1 Loss is Associated with Genomic Instability of Endometrial Cancer

Abstract Objective: Endometrial cancer is a common gynecologic malignancy, yet carcinogenesis remains elusive. Evidence showed that aberrant genomic methylation profiling contributes to the development of endometrial cancer. G protein-coupled estrogen receptor (GPER1), a membrane-associated estrogen receptor, was reported to play a multifaceted role in tumors. Its function in endometrial cancer is little known. Here, we conducted an integrated analysis of RNA expression, DNA methylation, and somatic mutations data from TCGA to investigate GPER1 upstream regulator and its influence in endometrial cancer biological process. Methods: RNA-seq, DNA methylation, and clinical information of endometrial cancer (n=554) and normal control (n=33) were obtained from TCGA database. RNA-seq profiles of GPER1 low and high groups were analyzed by R 4.1.0 software. KEGG and GSEA based on GPER1 expression were conducted. Correlation analysis of GPER1 and genomic instability were displayed. G1, the GPER1 agonist, was added to observe cell viability and metastatic ability in vitro. DNA methylation data was analyzed. Results: GPER1 expression was decreased in endometrial cancer compared with normal tissues. GPER1 was associated with poor overall survival (HR=0.52, p=0.003) (Figure 1). Low expression group showed a more frequent mutation landscape, higher tumor mutation burden (TMB), and micro-satellite instability (MSI) (Figure 2). Several hypermethylation loci on GPER1 CpG island were revealed. Methylation status is negatively correlative to RNA expression of GPER1 (Figure 3). P-value <0.05 and log2FC >1.5, 473 up-regulated and 114 down-regulated genes were screened. Up-regulated DEGs enriched in the Estrogen signaling pathway, Endometrial cancer, wnt signaling pathway, etc. Down-regulated DEGs enriched in Cell cycle, p53 signaling pathway, etc. (Figure 4). GSEA analysis showed that GPER1 low expression group was enriched in several biological processes including cell cycle checkpoint, Recombinational repair, etc. G1 inhibited endometrial cancer cell growth in a dose-dependent manner, and reduced cell metastatic ability (Figure 5). Conclusions: GPER1 exhibited decreased expression in endometrial cancer and DNA hypermethylation in promoter CpG island locus. The low GPER1 expression group showed prominent genomic instability. GPER1 agonists inhibit endometrial cancer cell growth and metastasis, which may serve as a therapeutic target. Citation Format: Xuan Feng, Ting Huang, Boqiang Shen, Juan Hao, Jiaqi Wang, Yangyang Dong, Jingyi Zhou, Jianliu Wang. Integrative genomic analysis reveals hypermethylation triggered GPER1 loss is associated with genomic instability of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5686.