Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery
Lymphedema (LE) is a frequent complication of breast cancer treatment. LE is caused by a disruption in the lymphatic system that results in the accumulation of fluid in the interstitial space.1 LE manifests as swelling of the affected limb and is associated with chronic pain, disfigurement, reduced mobility, functional impairment, predisposition to infections, and increased health care costs.2–5
The true incidence of breast cancer-related LE is unknown, though estimates range from 6% to 83%.6 This wide variation is due to differences in diagnostic criteria, measurement techniques, timing of measurements, duration of follow-up, and sample characteristics.7,8 In a recent review of 11 prospective cohort studies,9 the median incidence rate for LE within 3 years of breast cancer treatment was 20%. In the United States, this rate would mean that more than 500,000 breast cancer survivors are affected by this incurable condition.10
Research is often directed at identifying risk factors for LE with the hope of developing interventions to reduce its incidence.11 In our previous study,12 we identified both phenotypic and genotypic differences between women who did and did not develop LE following breast cancer treatment. The phenotypic characteristics associated with LE were increased body mass index (BMI), increased number of lymph nodes removed, higher stage of disease, and having had a sentinel lymph node biopsy (SLNB). In addition, a number of candidate genes in the lymphatic and angiogenesis pathways were identified as being associated with LE (i.e., lymphocyte cytosolic protein 2 (LCP2), neuropilin-2 (NRP2), protein tyrosine kinase (SYK), Forkhead box protein C2 (FOXC2), vascular cell adhesion molecule 1 (VCAM1), and vascular endothelial growth factor C (VEGFC)). While this study was novel in uncovering associations between LE and lymphatic and angiogenic candidate genes, further investigation is warranted to identify additional molecular pathways.
Several studies have suggested that cytokines may be involved in the pathophysiology of LE.13,14 Cytokines play a key role in modulating inflammatory responses, which may subsequently lead to lymphatic dysfunction and LE.13 In a study that used a specific bioassay and performed transcriptional microarray analysis on human skin,15 a number of cytokine genes (i.e., interleukin (IL) 4, IL6, IL10, IL13) were upregulated in LE specimens. In another study that investigated the role of inflammation in the regulation of fibrosis and lymphatic dysfunction,14 the blockade of T-helper 2 cytokines, including IL-4 and IL-13, prevented T-cell differentiation and its subsequent inflammatory response in a mouse-tail model of LE. This blockade resulted in less fibrosis and improved lymphatic function. Findings from these studies suggest that variations in cytokine genes may account for some of the differences in the development of LE. Therefore, the purpose of this study was to determine if variations in pro-and anti-inflammatory cytokine genes were associated with the development of LE following breast cancer treatment.
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