TLR-4 genetic variants as predictive biomarkers for susceptibility and clinical outcomes in triple-negative breast cancer: A case control study

Abstract

Purpose: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC), with few effective therapy options. Toll-like receptor 4 (TLR-4) gene variants were linked to increased risk and progression of various cancers. We explored the relationship between TLR-4 polymorphisms and susceptibility to BC and TNBC among women in Tunisia.

Methods: A case-control study was conducted on 488 women diagnosed with BC, of whom 130 presented with TNBC, and a control group comprising 476 cancer-free women. Genotyping of rs2770150, rs2149356, rs1554973, and rs7856729 TLR-4 variants was done by real-time PCR. Multivariate logistic regression analyses and haplotype assessments evaluated their association with BC risk.

Results: The significantly reduced minor allele (MAF) and genotype frequencies of rs1554973 were revealed in women with BC, and a dose-dependent decrease in the BC risk was identified among women with rs1554973 genotypes. Conversely, significantly elevated rs1554973 and rs7856729 MAF were seen in TNBC cases, with a significant correlation between increased TNBC risk and rs2770150, rs1554973, and rs7856729. Multivariate analysis demonstrated a positive relationship between rs2770150 and BMI and oral contraceptive usage, while rs2149356 was positively correlated with menstrual patterns and miscarriages but inversely with menarche onset. The rs1554973 variant was positively correlated with BMI and live births but negatively with age at menarche, while rs7856729 was positively correlated with menarche and live birth but negatively to menopausal status. Four-locus TLR-4 haplotypes revealed negative correlations of TTTG, TGTG, TGTT, and CTCG haplotypes when associated with BC. In contrast, haplotypes TTTT and TTCG presented a positive and negative association with TNBC risk.

Conclusions: Results from this study underscore the correlation between TLR-4 SNPs and susceptibility to BC and the TNBC subtype. This imparts potential prognostic and diagnostic aspects for these gene variants in patients with BC and within specific patient subgroups.

Keywords: Allele; Breast cancer; SNP; Toll-like receptor-4; Triple negative breast cancer.