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. 2023 Jan;25(1):51-64.
doi: 10.1177/10998004221115863. Epub 2022 Aug 5.

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

Carolyn S Harris  1 , Christine A Miaskowski  1   2 , Yvette P Conley  3 , Marilyn J Hammer  4 , Anand A Dhruva  2 , Jon D Levine  2 , Adam B Olshen  2 , Kord M Kober  1
Affiliations

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

Carolyn S Harris et al. Biol Res Nurs. 2023 Jan.

Abstract

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-κB) 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-κB 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.

Keywords: DNA methylation; cancer; chemotherapy; gastrointestinal symptom cluster; inflammation; nausea.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Symptoms within the gastrointestinal symptom cluster. The size of each node represents the occurrence rate for that symptom in oncology patients in the week prior to their second or third cycle of chemotherapy (Harris, Kober, Cooper, et al., 2022). Note. DS = difficulty swallowing; VOM = vomiting.
Figure 2.
Figure 2.
Screenshot of the University of California Santa Cruz Genome browser (http://genome.ucsc.edu/) displaying cg03171795 on chromosome three of the hg19 (genome reference consortium Version 37) assembly of the human genome (Kent et al., 2002). Assembly tracks show scale, chromosome, and the hypermethylated status of cg03171795 and its genomic position as reported by the HAIB. Tracks denoting putative regulatory regions across multiple cell lines that were identified by ENCODE include: predicted chromatin state using an HMM; histone modifications for H3K4me1 and H3K4m1; DNase I hypersensitivity clusters; and levels of enrichment for the layered H3K4Me1 and H3K27Ac histone marks. For the three tracks that illustrate the ChromHMM for three cell lines, the orange color indicates a “strong enhancer” predicted chromatin state; yellow color indicates a “weak/poised enhancer” state; and light grey color indicates heterochromatin or low signal. For the H3K4Me1 and H3K27Ac marks, the coloring indicates the signal intensity from one of seven cell lines. Note. ChromHMM = chromatin state segmentation by multivariate Hidden Markov Modeling; ENCODE = Encyclopedia of DNA elements; GM12878 = B-lymphoblastoid cell line; H1-hESC = embryonic stem cells, line H1; H3K4me1 = histone H3 mono methyl K4; HAIB = Hudson Alpha Institute for Biotechnology; hg = human genome; HMM = Hidden Markov Model; HSMM = human skeletal muscle myoblasts; NT2-D1 = clonally derived, pluripotent human embryonal carcinoma cell line.
Figure 3.
Figure 3.
Protein-protein interaction network of predicted functional proteins for LTB. Network interaction representation for LTB was generated using the STRING database (Szklarczyk et al., 2019). Edges represent specific or meaningful associations. The colors of the edges connecting the nodes represent the types of evidence supporting the connections, namely: known interactions from experimental evidence (pink), predicted gene co-occurrence (blue), and co-expression (black). Note. LTA = lymphotoxin alpha; LTB = lymphotoxin beta; LTBR = lymphotoxin beta receptor; TNFRSF1A = tumor necrosis factor receptor super family 1 A; TNFRSF1B = tumor necrosis factor receptor super family 1 B; TRAF2 = tumor necrosis factor receptor associated factor 2; TRAF3 = tumor necrosis factor receptor associated factor 3; TRAF5 = tumor necrosis factor receptor associated factor 5.
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