Variations in Potassium Channel Genes Are Associated With Breast Pain in Women Prior to Breast Cancer Surgery

Abstract

Preoperative breast pain in women with breast cancer may result from a number of causes. Previous work from our team found that breast pain occurred in 28.2% of women (n=398) who were about to undergo breast cancer surgery. The occurrence of preoperative breast pain was associated with a number of demographic and clinical characteristics, as well as variation in two cytokine genes. Given that ion channels regulate excitability of sensory neurons, we hypothesized that variations in potassium channel genes would be associated with preoperative breast pain in these patients. Therefore, in this study we evaluated for associations between single nucleotide polymorphisms and inferred haplotypes among 10 potassium channel genes and the occurrence of preoperative breast pain in patients scheduled to undergo breast cancer surgery. Multivariable logistic regression analyses were used to identify those genetic variations that were associated with the occurrence of preoperative breast pain while controlling for age and genomic estimates of and self-reported race/ethnicity. Variations in four potassium channel genes: 1) potassium voltage-gated channel, delayed rectifier, subfamily S, member 1 (KCNS1); 2) potassium inwardly-rectifying channel, subfamily J, member 3 (KCNJ3); 3) KCNJ6; and 4) potassium channel, subfamily K, member 9 (KCNK9) were associated with the occurrence of breast pain. Findings from this study warrant replication in an independent sample of women who report breast pain following one or more breast biopsies.

Genetic insights toward improved management of chronic pain after mastectomy

“…6 Earlier work by the group also uncovered SNPs in GIRK1, GIRK2, and TASK3 connected to the occurrence of breast pain before surgery. 18 This reinforces the proposed involvement of these subunits in pain signalling and also provides a genetic correlate to the observation that preoperative breast pain is often a predictor of chronic pain after surgery. 16,25 It is not clear whether this early pain was acute or chronic, but the symptoms reported by patients hint toward a nociceptive rather than neuropathic nature.…”

“…Given that KCNS1 has been implicated in various human and animal pain syndromes, 4,11,30 including premastectomy pain in the same cohort, 18 it is possible that a larger sample would lower detection threshold. A related confounding factor is the intrinsic heterogeneity of the studied population, encompassing similar diagnoses but divergent molecular aetiologies.…”

Preoperative Breast Pain Predicts Persistent Breast Pain and Disability After Breast Cancer Surgery

“…Women with preoperative breast pain appear to be particularly at risk for more severe acute postoperative pain; impaired shoulder flexion; sensory loss at the breast scar site; and persistently poorer physical well-being. Based on our previous findings of associations between variations in cytokine 2 and potassium channel 39 genes and the occurrence of preoperative breast pain in this sample, it is reasonable to suggest that some of these patients are predisposed to experience preoperative breast pain. Future research that includes molecular characterization of both normal and diseased breast tissue from patients at the time of surgery, as well as a detailed phenotypic and sensory evaluation of preoperative breast pain, may provide insights into the mechanisms that underlie preoperative breast pain and suggest avenues for interventions to reduce the occurrence and severity of persistent postsurgical breast pain.…”

Potassium Channel Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery

“…In this same sample, different polymorphisms in both the GIRK1 and GIRK2 genes were associated with the occurrence of breast pain (Langford et al, 2015; Langford et al, 2014). Polymorphisms in the GIRK2 gene have been associated with postoperative pain, pain sensitivity, and addiction (Nishizawa et al, 2014).…”