Machine-learned analysis of global and glial/opioid intersection–related DNA methylation in patients with persistent pain after breast cancer surgery

Background: Glial cells in the central nervous system play a key role in neuroinflammation and subsequent central sensitization to pain. They are therefore involved in the development of persistent pain. One of the main sites of interaction of the immune system with persistent pain has been identified as neuro-immune crosstalk at the glialopioid interface. The present study examined a potential association between the DNA methylation of two key players of glial/opioid intersection and persistent postoperative pain. Methods: In a cohort of 140 women who had undergone breast cancer surgery, and were assigned based on a 3year follow-up to either a persistent or non-persistent pain phenotype, the role of epigenetic regulation of key players in the glial-opioid interface was assessed. The methylation of genes coding for the Toll-like receptor 4 (TLR4) as a major mediator of glial contributions to persistent pain or for the μ-opioid receptor (OPRM1) was analyzed and its association with the pain phenotype was compared with that conferred by global genome-wide DNA methylation assessed via quantification of the methylation in the retrotransposon LINE1. Results: Training of machine learning algorithms indicated that the global DNA methylation provided a similar diagnostic accuracy for persistent pain as previously established non-genetic predictors. However, the diagnosis can be based on a single DNA based marker. By contrast, the methylation of TLR4 or OPRM1 genes could not contribute further to the allocation of the patients to the pain-related phenotype groups. Conclusions: While clearly supporting a predictive utility of epigenetic testing, the present analysis cannot provide support for specific epigenetic modulation of persistent postoperative pain via methylation of two key genes of the glial-opioid interface