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.
Highlights
Breast cancer (BrCa) is the most common cancer morbidity among women worldwide and is especially prevalent in the US and other developed countries
CRITERIA FOR toll-like receptor (TLR) SIGNALING GENE AND single nucleotide polymorphism (SNP) SELECTION Toll-like receptor-associated genes and SNPs were selected using one or more of the following criteria: [1] epidemiological or molecular biological evidence from published reports indicating a relationship between the SNP/gene with cancer or inflammatory/immune response related diseases (Figure 1); [2] commonly studied loci; [3] marked disparities in genotype frequency comparing women of African descent to their Caucasian counterparts (i.e., ±10% change) (Table 1); [4] evidence demonstrating a link with alterations in mRNA expression/stability or protein expression/structure or function using in silico tools or published reports1; and [5] a minor allele frequency ≥1% reported in the National Center for Biotechnology Information (NCBI) Entrez SNP [24]2
For this pilot study based in Atlanta, GA, we enrolled 174 African-American women who had been diagnosed with BrCa or who possessed benign nodules
Summary
Breast cancer (BrCa) is the most common cancer morbidity among women worldwide and is especially prevalent in the US and other developed countries. Several factors contribute to BrCa risk, including age, family history of BrCa, personal history of benign breast disease, late menopause, obesity, high endogenous estrogen and testosterone levels, adult weight gain, early menarche and null parity, and BRCA 1/2 mutations. Specific mutations in BRCA1 and BRCA2 are associated with a genetic predisposition to BrCa. Specific mutations in BRCA1 and BRCA2 are associated with a genetic predisposition to BrCa These mutations account for only 5–10% of the reported BrCa cases [1]. Exploring the contribution of other genetic factors associated with BrCa is an active area of research [2].
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