Abstract
African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women’s Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.
Highlights
Breast cancer is the most common cancer among women in the United States, accounting for 29% of all newly diagnosed cancers [1]
Data on estrogen receptors (ER) status were available for 75.8% of European American (EA) cases and 72.5% of AA cases, and AA cases were more likely than EA cases to be diagnosed with ER negative breast cancer (20.1% versus 15.5%, P=0.007)
A number of genome-wide association (GWA) studies focused on breast cancer have been completed, and have identified novel genetic variants as potentially being associated with breast cancer risk [28]
Summary
Breast cancer is the most common cancer among women in the United States, accounting for 29% of all newly diagnosed cancers [1]. Elevated circulating levels of inflammatory biomarkers, i.e., IL6, TNFα, C-reactive protein (CRP), have been associated with a greater risk for several types of cancer and cancer prognosis, including breast [8,9]. Several studies have identified inflammation and immune-related signatures as being important for disease prognosis for triple negative breast cancer, the aggressive breast cancer subtype often observed in young AA women [10]. Because of evolution over millennia in Africa, and adaptation to endemic infectious diseases, it is possible that innate immune factors may differ by ancestry, with a more robust inflammatory response among AAs [13,14,15], which could contribute to the differential risk between AA and EA women of developing more aggressive breast cancer phenotypes
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