A Prospective Evaluation of the Association between a Single Nucleotide Polymorphism rs3775291 in Toll-Like Receptor 3 and Breast Cancer Relapse

Abstract

BackgroundToll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we 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 relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients.MethodsIn this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population.ResultsUnivariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P<0.01), but this finding was not observed with the dominant model (P = 0.31). The results remained significant after adjusting for the clinical parameters in the recessive model (HR = 3.53, 95% confidence interval [CI]: 1.98–6.31, P<0.01). Further survival analysis indicated that this SNP was significant in the luminal-B, triple-negative breast cancer (TNBC), and human epidermal growth factor receptor 2-positive (HER2+) patients using the recessive model but that it was not significant in the luminal-A patients. The SNP rs4833095 showed a non-significant tendency toward an increased RFS rate in the patients with the TT genotype.ConclusionOur results suggest that the SNP rs3775291 in TLR3 may influence patient outcome. Further studies with larger sample sizes should be conducted to validate our findings.

Association of gene polymorphisms of pattern‐recognition receptor signaling pathway with the risk and severity of hand, foot, and mouth disease caused by enterovirus 71 in Chinese Han population

“…This gene variation does not affect expression of TLR3 mRNA and protein, but reduces its ability to bind dsRNA, which affects TLR3‐mediated activation of nuclear factor (NF)‐κB . Its AA genotype is a risk genotype and is associated with infectious diseases, autoimmune diseases and tumors . TLR3 rs5743305 is located in the promoter region (−926) and may affect the transcriptional activity of TLR3 .…”

“…26 Its AA genotype is a risk genotype and is associated with infectious diseases, autoimmune diseases and tumors. 23,27 TLR3 rs5743305 is located in the promoter region (−926) and may affect the transcriptional activity of TLR3. Rs5743305 heterozygous variant is associated with an immune response following measles vaccine inoculation, which reduces antibody titer levels and immune responses.…”

Toll-Like Receptors Gene Polymorphism and Susceptibility to Cancer Development

“…with A allele is associated with an increased risk of relapse in breast cancer [33]. However, the same rs3775291 polymorphism has been associated with increased survival when diagnosed at stage II among German colorectal cancer patients [46].…”

“…Rs7696175 was found to be associated with increased risk of breast cancer in two populations: Chinese and of European ancestry (OR > 1) [31,32]. Moreover, Chen et al investigated the association of rs4833095 SNP and breast cancer in a Chinese population, and they found no association [33]. In colon cancer, rs5743618 (T1805G) on exon 4 results in I602S amino acid substitution in the junction of cytoplasmic and transmembrane TLR1 domain, affecting ligand binding [34].…”

Impact of Pattern Recognition Receptors on the Prognosis of Breast Cancer Patients Undergoing Adjuvant Chemotherapy

“…A SNP, rs3775291(1234 C>T), in TLR3 causing a single amino acid exchange (L412F) in the RNA-binding region of this receptor negatively influences the fate of patients with triple-negative or Her2 þ breast cancer (17) and colorectal carcinoma (18), as it increases or decreases natural resistance to infection by multiple viruses, including cytomegalovirus, human immunodeficiency virus-1, hepatitis C virus, and herpes simplex. rs3775291 reduces the expression and signaling function of TLR3 (19).…”