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. 2017 Nov:99:203-213.
doi: 10.1016/j.cyto.2017.07.006. Epub 2017 Jul 29.

Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery

Kimberly E Stephens  1 , Jon D Levine  2 , Bradley E Aouizerat  3 , Steven M Paul  4 , Gary Abrams  2 , Yvette P Conley  5 , Christine Miaskowski  6
Affiliations

Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery

Kimberly E Stephens et al. Cytokine. 2017 Nov.

Abstract

Persistent pain following breast cancer surgery is a significant problem. Both inherited and acquired mechanisms of inflammation appear to play a role in the development and maintenance of persistent pain. In this longitudinal study, growth mixture modeling was used to identify persistent breast pain phenotypes based on pain assessments obtained prior to and monthly for 6months following breast cancer surgery. Associations between the "no pain" and "mild pain" phenotypes and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. The methylation status of the CpG sites found in the promoters of genes associated with pain group membership was determined using bisulfite sequencing. In the multivariate analysis, three SNPs (i.e., interleukin 6 (IL6) rs2069840, C-X-C motif chemokine ligand 8 (CXCL8) rs4073, tumor necrosis factor (TNF) rs1800610) and two TNF CpG sites (i.e., c.-350C, c.-344C) were associated with pain group membership. These findings suggest that variations in IL6, CXCL8, and TNF are associated with the development and maintenance of mild persistent breast pain. CpG methylation within the TNF promoter may provide an additional mechanism through which TNF alters the risk for mild persistent breast pain after breast cancer surgery. These genetic and epigenetic variations may help to identify individuals who are predisposed to the development of mild levels of persistent breast pain following breast cancer surgery.

Keywords: Breast cancer; C-X-C motif chemokine ligand 8; Cytokine genes; DNA methylation; Epigenetics; Interleukin 6; Persistent pain; Post-mastectomy pain; Post-surgical pain; Tumor necrosis factor.

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Conflict of interest statement

Conflict of interest statement: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Deoxyribonucleic acid (DNA) methylation at the promoter region of the interleukin 6 (IL6) gene. (A) Scaled schematic representation of the 5’ untranslated region of the IL6 gene showing the distribution of CpG sites (vertical lines) and regions (horizontal bars) amplified using polymerase chain reaction. Nucleotide positions in relation to predicted translation start site are provided from GRCh37.p9 Primary Assembly; NM_000600.3. Two regions of the IL6 gene promoter were assessed. Region I assessed the percent methylation of c.-1162C, c.-1159C, c.-1157C, c.-1132C, c.-1124C and c.-1120C. Region II assessed the percent methylation of c.-729C, c.-727C, c.-691C, c.-673C, and c.-637C. The c.-1064C locus was not assayed. The association of the methylation level at c.-1120C and pain group membership was not evaluated because this site was 100% methylated for all samples. Locations of the amplified regions of the bisulfite-modified genome are shown as horizontal bars above the promoter. (B) DNA methylation levels of the promoter regions for IL6. Abbreviations: na, not assayed
Figure 2
Figure 2
Deoxyribonucleic acid (DNA) methylation at the promoter region of the C-X-C motif chemokine ligand 8 (CXCL8) gene. (A) Scaled schematic representation of the 5’ untranslated region of the CXCL8 gene showing the distribution of CpG sites (vertical lines) and region (horizontal bars) amplified using polymerase chain reaction. Nucleotide positions in relation to predicted translation start sites are provided from GRCh37.p9 Primary Assembly; NM_000584.3. Primer binding sites are shown (arrows). (B) DNA methylation levels of the promoter region for CXCL8.
Figure 3
Figure 3
Deoxyribonucleic acid (DNA) methylation at the promoter region of the tumor necrosis factor alpha (TNF) gene. (A) Scaled schematic representation of the 5’ untranslated region of the TNF gene showing the distribution of CpG sites (vertical lines) and region (horizontal bars) amplified using polymerase chain reaction. Nucleotide positions in relation to predicted translation start sites are provided from GRCh37.p9 Primary Assembly; NM_000594.3. Primer binding sites are shown (arrows). (B) DNA methylation levels of the promoter region for TNF. Asterisks indicates statistical significance at p2) of methylation levels between CpG sites. The value of r2 multiplied by 100 is provided within each box. The degree of shared variance was color-coded to indicate high (red) to none (white) with intermediate values rendered in pink. 5’ 3’
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