Background: African American (AA) women have lower incidence, but higher mortality rates when they are diagnosed with breast cancer. Biological differences in tumor subtypes, with greater prevalence of aggressive basal-like breast cancers in AA women, explain some disparities; however, even when AA women are diagnosed with ‘good prognosis’ Luminal A breast cancers, they fare worse than Caucasian (Cau) women with the same subtype. Our goal was to identify disparity-associated gene expression in breast tumors overall, and in Luminal A breast cancers specifically.
Methods: Disparity-associated gene expression was defined as gene expression that was both strongly associated with patient race and with substantial differential in disease-free survival in Cau, defined as the hazard ratio (HR) > 1.25 or < 0.8 comparing patients with >= median expression to those with < median expression. We used microarray data from 165 breast tumor samples (108 Cau and 57 AA women). This dataset included 68 Luminal A tumors and 39 Basal-like tumors. We identified race-associated gene expression using linear models with a false discovery rate (FDR) less than 5%. Genes that were differentially expressed by race in breast cancers overall or among luminal A tumors were tested for associations with survival. Genes that were both race- and survival-associated were further evaluated for race-related patterns of expression in normal reduction mammoplasty samples (N=100) and cancer-adjacent histologically normal (N=92) tissue.
Results: At an FDR = 5%, 10 genes were differentially expressed by race in Luminal A tumors. Six of these showed associations with survival [CRYBB2 (HR = 1.36), PSPH (HR = 1.65), ACOX2 (HR = 0.65), MUC1 (HR = 0.65), TYMS (HR = 2.67), SQLE (HR = 1.98)] in NKI295. Two distinct patterns emerged for the expression of these genes in normal tissue: CRYBB2 and PSPH were differentially expressed in tumor and normal tissue of AA compared to Cau women; ACOX2, MUC1, TYMS, SQLE were only differentially expressed in tumors. A composite expression score based on expression of all six genes, or including only CRYBB2/PSPH, was associated with tumor characteristics. Furthermore, composite expression was associated with survival across all tumors and Luminal A tumors in an independent dataset.
Discussion: These analyses replicated previously reported associations between CRYBB2 and PSPH expression in breast tumors and race, and extended the analysis to address normal tissue differences and survival among Luminal A tumors. These patterns in normal tissue suggest that CRYBB2 and PSPH expression could represent race-specific differences in susceptibility to aggressive tumors. Although disparities in luminal A breast cancer mortality may be related to treatment or access to care, these data suggest that biological differences between at-risk AA and Cau women may also be operating.
Citation Format: Monica E. D’Arcy, Whitney R. Robinson, Erin Kirk, Keith D. Amos, Charles M. Perou, Jodie M. Fleming, Melissa A. Troester. Race-associated gene expression in tumors and breast cancer mortality disparities. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-292. doi:10.1158/1538-7445.AM2014-LB-292