A Prospective Evaluation Of The Association Between A Single Nucleotide Polymorphism Rs3775291 In Toll-Like Receptor 3 And Breast Cancer Relapse

Background: Toll-like receptors(TLRs) regulate the balance between innate and adaptive immune response. Persistent inflammatory conditions produce cytokines and chemokines which can promote angiogenesis, metastasis, and subversion of adaptive immunity, thus, imbalances between inflammatory and immune-associated proteins contribute to cancer and disease progression. Missense single nucleotide polymorphisms(SNPs) in TLRs might be potentially functional and subsequently influence the risk of chronic infection and cancer development. We here investigated the association of two missense SNPs, rs3775291(c.1234G>A) in the TLR3 gene and rs4833095(c.743T>C) in the TLR1 gene, with the relapse-free survival(RFS) of patients with breast cancer in a cohort of prospectively observed patients. Methods: In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population. Univariate and multivariate Cox regression analysis were used to investigate the association between SNPs and RFS. Results: In a univariate analysis, patients with the AA genotype of rs3775291 were associated with a shorter RFS for breast cancer compared with those carrying the G allele in the recessive model(P<0.01) rather than in the dominant model(P=0.31). The results remained significant after adjusting for the clinical parameters, which includes lymph node status, tumor size, chemotherapy, endocrine therapy, and ER, PR, and HER2 status in the recessive model(HR=3.53, 95% confidence interval [CI]: 1.98-6.31, P<0.01). In the co-dominant model, the RFS rate for the AG genotype was almost the same as that for the GG genotype(AG vs. GG: HR=1.01, 95%CI: 0.59-1.75, P=0.96), and patients with the AA genotype presented an obviously shorter RFS compared with those with the GG genotype(AA vs. GG: HR=3.37, 95%CI: 1.74-6.51, P<0.01). A further survival analysis indicated that this SNP was significant in luminal-B, triple-negative breast cancer(TNBC), and human epidermal growth factor receptor 2-positive(HER2+) subtypes in the recessive model, but not in luminal-A patients. SNP rs4833095 had a non-significant tendency toward producing a better RFS rate with the TT genotype among all patients, no matter in univariate or multivariate analysis. Conclusion: Our results suggest that the SNP rs3775291 in TLR3 gene may influence patients’ outcome, especially in luminal B, TNBC, and HER2+ subtypes. In the mean time, the role of SNP rs4833095 needs deeper work. Because a SNP is a germline variation that can be directly detected from a patient’s blood sample, it may serve as a clinical prognostic marker of malignances. Larger sample sizes should be conducted to validate our findings. Further validation work and a feasibility study are required before the results of this study be considered for clinical use.