P478 - LBA_ECE_1368 - Remodelling of GPCR expression in endometrial cancer highlights KISS1R as a candidate receptor

Abstract

G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and play central roles in mediating extracellular signaling, including hormonal, metabolic, and microenvironmental cues. Increasing evidence indicates that aberrant GPCR expression contributes to cancer-associated processes such as proliferation, invasion, immune modulation, and metabolic adaptation. Moreover, recent pan-cancer studies suggest that this is highly tissue-specific and may reveal clinically relevant signaling signatures. Endometrial cancer is characterised by strong hormonal regulation and a dynamic tumour microenvironment, both of which are likely to influence GPCR-mediated signalling. However, the global GPCR expression profile in endometrial cancer remains poorly defined, limiting our understanding of this disease. The objective of this study is to define the differential expression profile of GPCRs in endometrial cancer based upon data generated by the TCGA Research Network. In this study, we performed a comprehensive bioinformatic analysis of GPCR expression in endometrial cancer using publicly available RNA-sequencing data from The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC). All analyses were performed using R Statistical Software (v4.5.2.). A paired analysis was conducted on 23 primary endometrial adenocarcinoma tumors and matched adjacent healthy endometrium tissues. Raw count data were processed using edgeR package (v4.0) with TMM normalization and logCPM transformation, followed by differential expression analysis with Benjamini–Hochberg false discovery rate (FDR) correction. Guide to Pharmacology GPCR list (v2025.3) excluding olfactory receptors was used to curate the GPCR list. After filtering, 17432 genes were retained, of which 10224 were significantly differentially expressed (FDR < 0.05). Among 402 genes from the curated GPCR list, 149 GPCRs were significantly differentially expressed in the paired analysis (FDR < 0.05). Notably, the majority of differentially expressed GPCRs exhibited strong down-regulation with large effect sizes, whereas a smaller subset of receptors showed consistent up-regulation across patients. Among the most significantly upregulated receptors, KISS1R emerged as a top candidate (logFC ≈ 4.06, FDR ≈ 2.3×10⁻⁷), alongside other GPCRs linked to diverse signaling pathways. Exploratory analysis stratified by tumour grade indicated a tendency for increased expression of selected GPCRs, including KISS1R, in higher-grade tumours, although this observation requires further validation. Overall, these findings reveal a pronounced remodeling of the GPCR expression landscape in endometrial cancer, characterized by widespread receptor down-regulation and selective up-regulation of specific GPCRs. This study provides a systematic framework for understanding GPCR dysregulation and highlights candidate GPCRs for future functional and translational investigation.