The opioid receptor-ligand network in human cancers: pan-cancer multi-omics profiling and translational implications.

Abstract

Opioid receptor-ligand signalling has been implicated in tumour biology and perioperative outcomes; however, its pan-cancer molecular landscape and clinical relevance remain incompletely defined. We performed a pan-cancer multi-omics analysis of eight predefined opioid receptor-ligand genes across 33 tumour types from The Cancer Genome Atlas. Analyses included gene expression analysis using the linear models for microarray data (limma) package, genomic alterations, DNA methylation, regulatory network inference, pathway activity estimation using gene set variation analysis, and survival modelling. Multivariable Cox regression models were adjusted for age, sex, and tumour stage. Opioid receptor-ligand genes exhibited heterogeneous and generally low-to-moderate expression across tumour types. Genomic and epigenetic alterations were tumour-specific and variably associated with gene expression. Selected genes showed associations with overall survival in a tumour-dependent manner; however, these associations were attenuated after adjustment for clinical covariates and were accompanied by wide confidence intervals in some cohorts. Pathway analyses suggested associations with broader biological programmes, including epithelial-mesenchymal transition and immune-related pathways. Regulatory analyses identified candidate transcription factors and miRNAs, although these findings are exploratory. This pan-cancer analysis provides a systematic overview of opioid receptor-ligand gene features across human cancers. The observed associations are context-dependent and should be interpreted as hypothesis-generating. Further mechanistic and prospective studies are required to determine the clinical relevance of opioid signalling in cancer and perioperative settings.