Two‐pore Domain Potassium Channel Genes and Breast Cancer in The Cancer Genome Atlas

The overarching goal of this dissertation was to systematically evaluate molecular markers (DNA methylation, gene expression, and copy number changes) of K2P channel genes in relation to breast cancer subtype, clinical covariates and prognosis, using a landscape approach in TCGA breast cancer data. Findings show that overexpression of KCNK5, KCNK9, KCNK10 and KCNK12, and underexpression of KCNK6 and KCNK15, are significantly associated with our primary outcome of TN subtype. Similar patterns of association were also evident for most of the related secondary subtype outcomes. We found CG loci to be associated with nH black race: 4 loci in the promoter region of KCNK15, and 3 more loci near KCNK4, and 2 near KCNK5. CG loci on KCNK2, KCNK5 and KCNK9 were significantly associated with negative expression across all hormone-receptor negative related subtype outcomes. Another locus near KCNK12 also had consistent correlations with positive gene expression across most hormone receptor related negative subtypes. In addition, copy number loss in KCNK10, KCNK13, KCNK16 and KCNK18, and gain in KCNK3, KCNK4, KCNK5, KCNK6, KCNK7, KCNK9, KCNK12, KCNK16, KCNK17 and KCNK18, were common associations across hormone receptor negative subtypes. We found K2P markers together accounted for, or mediated, a substantial proportion of the observed subtype disparity (i.e. increased risk of ER/PR-negative/TN disease) in black women, and gene methylation accounted for the largest proportion mediated. K2P gene markers together also mediated a substantial part of the molecular ER/PR-negative/TN subtype disparity observed with p53 expression. Finally, KCNK4 and KCNK9 may be associated with worse survival. Our study findings are however considered preliminary and need to be validated in additional studies.