Sequence Variants ofToll-Like Receptor 4Are Associated with Prostate Cancer Risk

Abstract

Inflammation has been implicated as an etiological factor in several human cancers. Growing evidence suggests that chronic inflammation may also play a role in the etiology of prostate cancer. Considering that genetic susceptibility is a major risk factor for this disease, we hypothesize that sequence variants in genes that regulate inflammation may modify individual susceptibility to prostate cancer. The lipopolysaccharide receptor Toll-like receptor 4 (TLR4) is a central player in the signaling pathways of the innate immune response to infection by Gram-negative bacteria and is an important candidate inflammatory gene. We performed a systematic genetic analysis of TLR4 sequence variants by evaluating eight single-nucleotide polymorphisms that span the entire gene among 1383 newly diagnosed prostate cancer patients and 780 age-and residencematched controls in Sweden. We found an association between a sequence variant (11381G/C) in the 3-untranslated region of the TLR4 gene and prostate cancer risk. The frequency of the variant genotypes (CG or CC) was significantly higher in the patients (24.1%) than in the controls (19.7%; P ‫؍‬ 0.02). The frequency of risk genotypes among patients diagnosed before the age of 65 years was even higher (26.3%). Compared with men who had the wild-type genotype of this single-nucleotide polymorphism (GG), those with GC or CC genotypes had a 26% increased risk for prostate cancer (odds ratio, 1.26; 95% confidence interval, 1.01-1.57) and 39% increased risk increased risk for early onset prostate cancer (before age 65 years; odds ratio, 1.39; 95% confidence interval, 1.02-1.91). The risk attributable to this variant for prostate cancer in Sweden was estimated to be 4.9%. Although the biological mechanism of the observed association remains to be elucidated, our finding supports a role for a bacteria-associated response pathway, possibly acting via inflammation, in the development of prostate cancer.

Inflammation in prostate carcinogenesis

“…Ten members of the human TLR family have been identified, and for most of these, specific classes of ligands, typically microbial components or surrogates thereof, have been identified and characterized. Recently, sequence variants in several TLR genes have been linked to prostate cancer risk, including TLR4 and the TLR1-6-10 gene cluster 114,115 .…”

“…Ten members of the human TLR family have been identified, and for most of these, specific classes of ligands, typically microbial components or surrogates thereof, have been identified and characterized. Recently, sequence variants in several TLR genes have been linked to prostate cancer risk, including TLR4 and the TLR1-6-10 gene cluster 114,115 .Ligands that are recognized by TLR4 include Gram-negative bacterial products, including lipopolysaccharide 116 , and human heat shock protein 60 (HSP60) 117 . In the CAPS study 114 found to be associated with prostate cancer risk.…”

“…Recently, sequence variants in several TLR genes have been linked to prostate cancer risk, including TLR4 and the TLR1-6-10 gene cluster 114,115 .…”

“…However, no specific ligand has been identified for TLR10. The TLR1 and TLR6 proteins each form heterodimers with TLR2 to establish a combinational repertoire that distinguishes a large number of PAMPs 120,122,123 .A study of the TLR1-6-10 cluster in prostate cancer patients in CAPS identified an association of sequence variants in TLR1-6-10 with prostate cancer risk 114,115 . The allele frequencies of 11 of the 17 SNPs examined in this gene cluster were significantly different between case and control subjects (P = 0.04-0.001), with odds ratios for variant allele carriers (homozygous or heterozygous) compared with wild-type allele carriers ranging from 1.20 (95% CI = 1.00-1.43) to 1.38 (95% CI = 1.12-1.70).…”

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

“…Zheng et al (2004) (Sun et al, 2005). An escalating mass of experimental evidence suggests that the neoplastic process may sabotage TLR signalling pathways to advance cancer progression.…”