Gastrointestinal Symptom Cluster is Associated With Epigenetic Regulation of Lymphotoxin Beta in Oncology Patients Receiving Chemotherapy

Objectives While the gastrointestinal symptom cluster (GISC) is common in patients receiving chemotherapy, limited information is available on its underlying mechanism(s). Emerging evidence suggests a role for inflammatory processes through the actions of the nuclear factor kappa B (NF-kappa B) signaling pathway. This study evaluated for associations between a GISC and levels of DNA methylation for genes within this pathway. Methods Prior to their second or third cycle of chemotherapy, 1071 outpatients reported symptom occurrence using the Memorial Symptom Assessment Scale. A GISC was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using EPIC (n = 925) and 450K (n = 146) microarrays. Trans expression-associated CpG (eCpG) loci for 56 NF-kappa B signaling pathway genes were evaluated. Loci significance were assessed using an exploratory false discovery rate (FDR) of 25% for the EPIC sample. For the validation assessment using the 450K sample, significance was assessed at an unadjusted p-value of 0.05. Results For the EPIC sample, the GISC was associated with increased expression of lymphotoxin beta (LTB) at one differentially methylated trans eCpG locus (cg03171795; FDR = 0.168). This association was not validated in the 450K sample. Conclusions This study is the first to identify an association between a GISC and epigenetic regulation of a gene that is involved in the initiation of gastrointestinal immune responses. Findings suggest that increased LTB expression by hypermethylation of a trans eCpG locus is involved in the occurrence of this cluster in patients receiving chemotherapy. LTB may be a potential therapeutic target for this common cluster.