IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women

Abstract

Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA, USA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology. Inheritance of the TLR3 rs10025405 GG genotype was associated with an 82% decrease in BrCa risk. In contrast, individuals who possessed at least one IRAK4 rs4251545 T allele had a 1.68- to 4.99-fold increase in the risk of developing BrCa relative to those with the referent genotype (OR = 4.99; 95% CI = 1.00, 25.00; p = 0.0605). However, the IRAK4 rs4251545 locus was only significant under the additive genetic model (p trend = 0.0406). In silico predictions suggest IRAK4 rs4251545 SNP falls within a transcription enhancer/silencer region of the gene and codes for an Ala428Thr amino acid change. This missense mutation introduces a potential phosphorylation site in the extreme carboxy terminus (XCT) of the IRAK4 kinase domain. Preliminary molecular modeling predicts that this SNP stabilizes two alpha helices within the XCT on the surface of the IRAK4 kinase domain and increases the size of the groove between them. Our in silico results, combined with previous reports noting the presence of IRAK4 and XCT fragments in mouse and human serum, suggest the possibility that the XCT subdomain of IRAK4 possesses biological function. These findings require further evaluation and validation in larger populations, additional molecular modeling as well as functional studies to explore the role of IRAK4 and its XCT in cell transformation and innate immunity.

Functional Polymorphisms in IRAKs Are Related to Hepatocellular Carcinoma Risk in Chinese Population

“…Our results were consistent with a previous study which found that rs4251545 was associated with 1.68- to 4.99-fold increases in the risk of developing breast cancer in African-American women [ 16 ]. Moreover, rs4251545 locus occurred in an enhancer/silencer region of the gene, which might impact IRAK4 transcriptional level.…”

Expression profile of Toll‑like receptors in human breast cancer

“…it has previously been reported that Tlr3 sequence variants may reduce 82% of breast cancer risk among african-american women (29), and the activation of Tlr3 was associated with a significant decrease in the risk of metastatic relapse in 194 patients with breast cancer, suggesting an association between clinical outcome and Tlr3 expression (26). This is consistent with the results of the present study, which revealed lower levels of Tlr3 expression in more malignant subtypes.…”

Prognostic and Predictive Value of DAMPs and DAMP-Associated Processes in Cancer

“…SNPs affecting TLR3 have been shown to influence prognosis in cohorts of 582 patients with CRC, especially among untreated individuals with Stage II disease ( 115 ) and 568 NSCLC patients ( 116 ). Along similar lines, TLR3 SNPs have been associated with an altered risk for cervical cancer amongst 330 Tunisian women ( 117 ), breast carcinoma amongst 174 African-American women ( 118 ), oral squamous cell carcinoma amongst 197 individuals ( 119 ) HCC amongst 948 subjects ( 120 ), and CRC amongst more than 5,000 individuals ( 121 ). A type I IFN-related transcription signature centered around the expression of MX dynamin-like GTPase 1 ( MX1 ) has been shown to predict the likelihood of 50 breast carcinoma patients to respond to neo-adjuvant anthracycline-based chemotherapy ( 39 ).…”