Innate immunity-related sequence variants as predictors of breast cancer risk among women of African descent.

Abstract

1581 Background: Recent advances demonstrate a relationship between chronic/recurrent inflammation and complex diseases. In breast cancer, it has been suggested that chronic or recurrent inflammation, attributed to persistent exposure to pathogens may alter the tissue microenvironment that favors tumor growth. The risk for breast cancer (BrCa) may be related to having a natural selective advantage toward inheriting innate immunity signaling loci linked with a proinflammatory response. However, it is unknown whether these variant innate immunity-related alleles will explain the BrCa risk and disease severity among women of African descent. The current study evaluated the individual effects of 14 innate immunity genes (TLR 1-4 CD14 IRAK2 IRAK4 IRF3 IRF5 MYD88 OAS1 TICAM1 TOLLIP RNAseL) in relation to breast cancer and tumor behavior among 200 African American female patients. We hypothesized that individuals inheriting high-risk innate immunity loci (linked with elevated inflammatory response or cell survival) will have an increased risk of developing BrCa or aggressive tumor subtypes relative to those with the referent genotypes. Methods: Twenty genetic alterations were evaluated in germ-line DNA samples collected from 108 patients and 92 disease-free individuals using SNPstream. All study participants were recruited from Grady Memorial Hospital and Emory Midtown Hospital in Atlanta, Georgia. We evaluated the independent effects of 20 variant innate immunity genes in relation to BrCa risk and tumor characteristics (tumor stage/size/pathology, hormone receptor status, and HER2 neu status) using a case-control and case-only study designs, respectively. Results: Inheritance of the IRAK4 rs4251525 TT genotype was associated with a statistically significant two-fold increase in BrCa risk [OR = 2.23; 95%CI = 1.24, 3.98; p = 0.007; p-trend = 0.0021]. Unfortunately, none of the markers were associated with advanced disease or other tumor characteristics. Conclusions: A non-synonymous sequence variant detected in IRAK4 (Ala >Thr) may serve as an important BrCa detection tool among women of African descent. Subsequent analyses are currently underway within a larger sub-population study set. No significant financial relationships to disclose.