Abstract B49: The role of KCNK9 and TP53 on the racial disparity in biologically aggressive breast cancer subtype in The Cancer Genome Atlas (TCGA)

Abstract

Abstract Introduction: Compared to non-Hispanic (nH) white, nH black women are more likely to present with biologically aggressive estrogen and progesterone receptor (ER/PR)-negative (ERN) and triple negative (TN) breast cancer subtypes which are associated with worse prognosis (black:white disparity). These subtypes also exhibit greater genetic instability, with TP53 being the single most recurrently mutated gene. KCNK9 is a maternally imprinted and functionally mono-allelic 2-pore domain potassium channel proto-oncogene located at chromosomal region 8q24.3, encoding TASK-3. KCNK9 overexpression may arise via loss of methylation (LOM) or copy number amplification (CNA). We examined KCNK9 and TP53 as potential mediators of the black:white racial disparity in aggressive breast cancer subtypes. Methods: Using publically available TCGA data on 1040 women with invasive breast cancer, we examined: associations of KCNK9 LOM (HM450 beta values; highest third loss vs. others), amplification (putative CNA from GISTIC; any vs. neutral), and mRNA overexpression (RNA-Seq from RSEM; z-score > +1 SD vs. others) with ERN and TN subtype, and overall survival (OS) and disease-free survival (DFS). General TP53 pathway function was examined using mRNA expression z-scores for six related genes (TP53 MDM2 MDM4 CDKN2A CDKN2B TP53BP1). Prevalence risk ratios (RRs) with 95% confidence intervals (CIs) were estimated via logistic regression with model-based standardization (predictive margins) and hazard ratios (HRs) using Cox proportional hazards models, and all models were adjusted at baseline for age as a continuous variable and stage as categorical variable. In mediation analysis, we estimated the proportionate reduction in the racial disparity in aggressive subtypes after accounting for differences in KCNK9 and TP53 pathway biomarkers by comparison of rescaled coefficients using the method of Karlson, Holm and Breen in adjusted models. Death from any cause was considered an event for all-cause mortality (i.e. OS), and recurrence or progression of disease was considered an event for DFS. Results: KCNK9 LOM, amplification and overexpression were each significantly associated with ERN and TN subtype and black race (all p<0.05). In mutually adjusted models including TP53 pathway markers and race, KCNK9 status significantly predicted outcome for both subtypes suggesting the importance of KCNK9 as a molecular driver of aggressive subtype (ERN: LOM RR, 3.69; 95% CI, 2.28-5.98; p<0.001. Amplification RR, 1.40; 95% CI, 0.98-1.99; p=0.064. Overexpression RR, 1.33; 95% CI, 1.07-1.67; p=0.011) (TN: LOM RR, 3.37; 95% CI, 1.99-5.70; p<0.001. Amplification RR, 1.82; 95% CI, 1.12-2.95; p=0.016. Overexpression RR, 1.41; 95% CI, 1.11-1.80; p=0.005). In baseline adjusted Cox models, amplification and overexpression were associated with greater OS, and overexpression was marginally associated with DFS. However, in mutually adjusted Cox models including subtype and TP53 pathway markers, no KCNK9 markers remained independent predictors of mortality or recurrence; however, TN subtype and CDKN2A overexpression remained significant predictors for both (TN: OS HR, 8.96; 95% CI, 2.65-30.28; p<0.001. DFS HR, 8.58; 95% CI, 2.24-32.8; p=0.002) (CDKN2A: OS HR, 0.29; 95% CI, 0.09-0.97; p=0.045. DFS HR, 0.21; 95% CI, 0.06-0.76; p=0.017). ERN and TN subtypes were more common among black patients (black:white disparity: ERN RR, 2.16; 95% CI, 1.6-2.8; p<0.001. TN RR, 2.54; 95% CI, 1.8-3.53; p<0.001). The racial disparity in ERN and TN subtypes was mediated by molecular pathways as follows: KCNK9 variables accounted for about one-third, TP53 pathway variables accounted for one-half, and together they accounted for more than two-thirds of the disparity (all p<0.05). Conclusions: KCNK9 appears to be a molecular driver of aggressive breast tumor subtype, and in combination with aberrant TP53 pathway overexpression, largely accounts for observed black:white disparity in more biologically aggressive breast cancer subtypes. Citation Format: Keith A. Dookeran, Jacob K. Kresovich, Maria Argos, Garth H. Rauscher. The role of KCNK9 and TP53 on the racial disparity in biologically aggressive breast cancer subtype in The Cancer Genome Atlas (TCGA). [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B49.