Associations of two-pore domain potassium channels and triple negative breast cancer subtype in The Cancer Genome Atlas: systematic evaluation of gene expression and methylation.

OBJECTIVES: It is unclear whether 2-pore domain potassium channels are novel molecular markers with differential expression related to biologically aggressive triple-negative type breast tumors. Our objective was to systematically evaluate associations of 2-pore domain potassium channel gene expression and DNA methylation with triple-negative subtype in The Cancer Genome Atlas invasive breast cancer dataset. Methylation and expression data for all fifteen 2-pore domain potassium family genes were examined for 1040 women, and associations with triple-negative subtype (vs. luminal A) were evaluated using age/race adjusted generalized-linear models, with Bonferroni-corrected significance thresholds. Subtype associated CpG loci were evaluated for functionality related to expression using Spearman's correlation. RESULTS: Overexpression of KCNK5, KCNK9 and KCNK12, and underexpression of KCNK6 and KCNK15, were significantly associated with triple-negative subtype (Bonferroni-corrected p < 0.0033). A total of 195 (114 hypomethylated and 81 hypermethylated) CpG loci were found to be significantly associated with triple-negative subtype (Bonferroni-corrected p < 8.22 × 10-8). Significantly negatively correlated expression patterns that were differentially observed in triple-negative vs. luminal A subtype were demonstrated for: KCNK2 (gene body: cg04923840, cg13916421), KCNK5 (gene body: cg05255811, cg18705155, cg09130674, cg21388745, cg00859574) and KCNK9 (TSS1500: cg21415530, cg12175729; KCNK9/TRAPPC9 intergenic region: cg17336929, cg25900813, cg03919980). CpG loci listed for KCNK5 and KCNK9 all showed relative hypomethylation for probability of triple-negative vs. luminal A subtype. Triple-negative subtype was associated with distinct 2-pore domain potassium channel expression patterns. Both KCNK5 and KCNK9 overexpression appeared to be functionally related to CpG loci hypomethylation.

Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities.

Evidence shows that both biological and nonbiological factors contribute to health disparities. Genetics, in particular, plays a part in how common diseases manifest themselves. Today, unprecedented advances in genetically based diagnoses and treatments provide opportunities for personalized medicine. However, disadvantaged groups may lack access to these advances, and treatments based on research on non-Hispanic whites might not be generalizable to members of minority groups. Unless genetic technologies become universally accessible, existing disparities could be widened. Addressing this issue will require integrated strategies, including expanding genetic research, improving genetic literacy, and enhancing access to genetic technologies among minority populations in a way that avoids harms such as stigmatization.

Race/ethnicity and disparities in mastectomy practice in the Breast Cancer Care in Chicago study.

PURPOSE: To examine racial/ethnic disparities in mastectomy practice and explore mediating factors to explain the disparity. METHODS: Participants included 989 females aged 30-79 years, from a population-based study of newly diagnosed (primary in situ/invasive) breast cancer patients, in Chicago, Illinois, from 2005 to 2008, who completed an interview. Medical records were also abstracted for tumor, diagnostic, and treatment information. Multivariable logistic regression models with model-based standardization were used to estimate risk differences. Differences in rescaled coefficients were used to estimate the proportion of the disparity that could be mediated by patient and tumor characteristics. RESULTS: Mastectomy prevalence overall was 40 %. Factors significantly associated with increased rates of mastectomy (p < 0.05) included the following: non-Hispanic (nH) black and Hispanic race/ethnicity; younger age at diagnosis; lower socioeconomic status (SES); lack of recency of and adherence to screening mammography; and higher tumor pathologic stage and grade. In adjusted models (age, body mass index, comorbidity), compared to nH white patients, mastectomy was increased by 10 % points in both nH black (95 % confidence interval [CI] 0.03, 0.18; p = 0.007) and Hispanic (95 % CI 0.01, 0.19; p = 0.028) patients. After accounting for the proportion of disparity mediated by tumor stage, the disparity was reduced by about a third in nH black (risk difference = 0.07, 95 % CI -0.01, 0.14) and half in Hispanic patients (risk difference = 0.04, 95 % CI -0.05, 0.13). Additional control for mediation by SES and other tumor-related factors almost completely eliminated the nH black:nH white disparity. CONCLUSIONS: The best approach to reducing the racial/ethnic disparity in mastectomy rates would be to intervene on factors that could affect stage at diagnosis.

Race and the prognostic influence of p53 in women with breast cancer.

BACKGROUND: Prior study suggests that p53 status behaves as an independent marker of prognosis in African American (AA) women with breast cancer. We investigate whether the influence of p53 is unique to AAs or is present in other race/ethnic groups, and how this compares with known prognostic factors. METHODS: Cox regression models [hazard ratios (HRs), 95% confidence intervals (CIs)] were used to select and evaluate factors prognostic for all-cause mortality in 331 AA and 203 non-AA consecutively treated women. RESULTS: Statistically significant baseline prognostic factors were as follows. For AAs: stage [(III/I) HR 5.57; 95% CI 3.08-10.09], grade [(higher/low) HR 1.55; 95% CI 1.14-2.11], estrogen receptor (ER)/progesterone receptor (PR) status [(-/+) HR 2.01; 95% CI 1.38-2.93], triple negative (ER-, PR-, HER2-) subtype [(+/-) HR 1.95; 95% CI 1.33-2.85], and p53 status [(+/-) HR 1.69; 95% CI 1.10-2.58]. For non-AAs: stage [HR 11.93; 95% CI 2.80-50.84], grade [HR 1.61; 95% CI 0.96-2.71], and ER/PR status [HR 2.13; 95% CI 1.19-3.81]. There was a differential effect of race within p53 groups (P=0.05) and in multivariate modeling p53-positive status remained an adverse prognostic factor in AAs only [HR 1.82; 95% CI 1.04-3.17]. Compared to non-AAs, 5-year unadjusted survival was worse for AAs overall (73.4% vs. 63.6%; P=0.032), and also for AAs with p53-positive status (80.3% vs. 54.2%; P=0.016), but not for AAs with p53-negative disease (68.4% vs. 67.9%; P=0.81). CONCLUSIONS: Among women with breast cancer of different race/ethnicity, an adverse prognostic effect as a result of p53 positivity was only observed in AA women.

p53 as a marker of prognosis in African-American women with breast cancer.

BACKGROUND: p53 overexpression has been identified as a poor prognostic marker in breast cancer. We investigate the value of p53 status within the context of stage and intrinsic subtype classification (subtype), in a group of African-American (AA) women of lower socioeconomic status (SES) with primary breast cancer. METHODS: Participants were 331 consecutive AA women treated at an urban hospital (median follow-up 41 months) with known subtype [luminal A = estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-; luminal B = ER+ and/or PR+, HER2+; HER2+ = ER-, PR-, HER2+; basal = ER-, PR-, HER2-, cytokeratin (CK)5/6+, and/or HER1+; and unclassified = negative for all five markers] and p53 (Pab1801 antibody) immunohistochemical status. Proportional hazards regression models were used to select and evaluate factors prognostic for all-cause mortality. RESULTS: p53+ status was associated with grade 3 tumors, ER/PR- status, and basal subtype. On univariate analysis, factors related to survival were stage, grade [(3/1) hazard ratio (HR) = 2.64; 95% confidence interval (CI), 1.15-6.07], subtype [(ex. basal/luminal A) HR = 2.15; 95% CI, 1.34-3.45], and p53 status [(+/-) HR = 1.77; 95% CI, 1.15-2.72]. Multivariable modeling indicated that p53+ status remained a negative prognostic factor (HR = 1.63; 95% CI, 1.01-2.59) after adjustment for effects of age, stage, grade, and subtype; 5-year adjusted survival was significantly greater for p53- (66.7%) than p53+ cases (54.7%). CONCLUSION: p53 status is an independent predictor of survival after consideration of other strong prognostic factors such as stage, tumor grade, and subtype, and thus may be useful in identifying AA women at high risk of breast cancer mortality.