Genetic Variation In Toll-like Receptors Research Articles

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Jiang et al., pp. 2480–2486 About 20% of patients with non-small-cell lung cancer respond well to treatment with the tyrosine kinase inhibitors gefitinib and erlotinib. The success of these drugs is dependent on activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase, which trigger inappropriate activation of anti-apoptotic signaling pathways and uncontrolled cell proliferation. However, the vast majority of tumors that initially respond to the treatment eventually become resistant. Some of the relapsed tumors acquire a secondary EGFR mutation that prevents binding of the drugs to the tyrosine kinase domain. Others show amplification of the MET proto-oncogene that induces EGFR-independent activation of downstream effector molecules. In this issue of IJC, Jiang and colleagues report on the discovery of a new mechanism by which non-small-cell lung cancers evade tyrosine kinase inhibitor treatment. In a study of six matched pretreatment and post-therapeutic lesions they show that some tumors are genetically heterogeneous for EGFR mutations. In pretreatment samples, they detected tumor cell clones expressing EGFR with activating mutations but also clones expressing wild-type EGFR. Initially, the wild-type clones are rare. However, during gefitinib treatment these clones selectively survive whereas clones with activating EGFR mutations decrease or completely disappear. Their results indicate that resistance to gefitinib treatment is more complex than initially thought; screening for EGFR genetic heterogeneity may help identify those cancer patients who respond best to the therapy. D'Agostini et al., pp. 2497–2502 Secondhand cigarette smoke, also known as environmental cigarette smoke (ECS), is generated by the smoking end of a cigarette and the smoke exhaled by smokers. It is passively inhaled by nonsmokers and can cause a wide range of adverse health effects. Previous studies showed that long-term exposure to ECS increases the development of lung tumors, a phenomenon attributed mainly to the gas phase of ECS. This study by D'Agostini and colleagues now uncovers a compelling link between ECS and light exposure and demonstrates that the carcinogenic properties of ECS can reach far beyond the respiratory tract. The TLR10-TLR1-TLR6 gene cluster on chromosome 4p14 and the location of the 28 single nucleotide polymorphisms (SNPs) genotyped in this study. The six SNPs marked in bold were significantly associated with reduced risk of prostate cancer. The authors exposed newborn Swiss albino mice to ECS (63 mg/m3 total suspended particulate for 6 h) during the first 4 months of their life, a treatment that triggered preneoplastic lesions in the lung as expected. However, these lesions did not progress to lung tumors unless the mice were also exposed to UV-A and UV-B-containing light emitted by halogen quartz bulbs. Exposure to light alone had no carcinogenic effect. In addition, exposure to ECS caused histopathological alterations in extra-respiratory organs, especially in the form of parenchymatous dystrophy of the liver, microadenomas and adenomas in the renal pelvis and the kidney, and papillomas in the urinary bladder. The authors speculate that light and smoke synergize in inducing DNA damage in the respiratory tract. They further point out that the liver of newborns is less efficient in clearing toxic products, possibly explaining the multiorgan effects of ECS in this study. Stevens et al., pp. 2644–2650 One in six men in the United States develops prostate cancer in his lifetime. Although it is the most common cancer among men, the insight into the risk factors and molecular causes remain limited. Previous studies revealed an association between the risk to develop prostate cancer and genetic variations in Toll-like receptors (TLR). TLRs are members of the interleukin-1 receptor superfamily and are an essential component of the innate arm of the immune system. Associations between TLR4 or the TLR10-TLR1-TLR6 gene cluster and prostate cancer have been described before but the results are highly controversial. Stevens and colleagues studied more than 1400 men with prostate cancer and the same number of controls enrolled in the American Cancer Society Cancer Prevention II Nutrition Cohort. They identified six single nucleotide polymorphisms within the TLR10-TLR1-TLR6 gene cluster that were significantly associated with a reduced risk of prostate cancer. Associations were found regardless of whether all cases or only advanced cases were analyzed, suggesting that the genetic variation influenced the initial development of prostate cancer rather than the progression of the disease. These findings strengthen the etiological link between chronic inflammation and prostate cancer. TLR1 and TLR6 recognize bacterial triacylated and diacylated lipoproteins, respectively, when heterodimerized with TLR2. No ligand has been identified for TLR10. It remains unclear how altered TLR functions modulate cancer risks. Increased TLR function could enhance anticancer immunity. Decreased activity may allow cancer cells to escape immune detection and elimination.

Maternal and fetal Toll-like receptor 4 genotype and chorionic plate inflammatory lesions

The objective of the study was to explore the relation between maternal and fetal genetic variation in Toll-like receptor 4 (TLR4) and chorionic plate inflammation In this prospective observational cohort of 109 women with singleton gestations, 13 tag single nucleotide polymorphisms (SNPs) were genotyped in the TLR4 gene. The diagnosis of chorionic plate inflammation was made by a single blinded perinatal pathologist. After adjustment for multiple comparisons, 1 maternal SNP (rs10759932) and 1 fetal SNP (rs1554973) in the TLR4 gene demonstrated highly significant association with chorionic plate inflammation. After adjustment for race, smoking, and bacterial vaginosis, carriage of these alleles was associated with chorionic plate inflammation (maternal rs1554973: odds ratio [OR] 5.2, 95% confidence interval, 3.2-6.4, P = .006; fetal rs10759932: OR 4.95, 95% confidence interval, 3.0-5.6, P = .005). There was no evidence of interaction between these 2 SNPs. Maternal and fetal genetic variation in TLR4 is strongly associated with chorionic plate inflammation. This maternal and fetal genotypic effect are independent of each other as well as other environmental covariates.

Genetic variation in the toll‐like receptor gene cluster (TLR10‐TLR1‐TLR6) and prostate cancer risk

Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29-38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations.

High-throughput microtiter well-based bioluminometric genotyping of two single-nucleotide polymorphisms in the toll-like receptor-4 gene

Toll-like receptors (TLRs) play a fundamental role in pathogen recognition and activation of innate immunity. Genetic variations in TLR have been associated with reduced host immune response to TLR ligands. We developed a rapid, simple and cost-effective method for identification of two common single-nucleotide polymorphisms (SNPs) within TLR4 gene in a high-throughput format. The method consists of a single polymerase chain reaction of the region spanning the A896G and C1196T polymorphic sites, followed by two primer extension reactions at each site using primers that carry a (dA) 24 segment at the 5′ end. A biotinylated nucleotide is incorporated in the extended primer. The products are captured in microtiter wells coated with streptavidin and detected using a (dT) 30-conjugated photoprotein aequorin. A total of 209 individuals were genotyped for each SNP. The A896G and C1196T polymorphisms were found to be in linkage disequilibrium; 186 individuals (89%) were wild-type homozygous (A/A or C/C), 22 (10.5%) were heterozygotes (A/G or C/T), and 1 (0.5%) was homozygous for the mutation (G/G or T/T). The accuracy of this method was confirmed by sequencing. The newly developed method may be useful for association studies of these two SNPs with several diseases.

The role of genetic variation in Toll-like receptor 4 in prostate cancer susceptibility: a review

Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response against invading pathogens. Recent association studies have identified genetic variants in TLR4 that appear to influence the risk of prostate cancer. To evaluate critically whether genetic variation in TLR4 influences prostate cancer susceptibility, a systematic review of the literature on TLR4 and prostate cancer is done. All genetic association studies of TLR4 and prostate cancer are evaluated. In particular, issues related to genetic coverage, study heterogeneity and multiple hypothesis testing are examined. Although all three of the published studies suggest that the TLR4 locus itself is associated with prostate cancer, there is no corroboratory evidence for which specific variants influence the risk of disease. Clearly, these studies alone cannot establish TLR4 as a prostate cancer susceptibility locus. By evaluating candidate genes such as TLR4 further in conjunction with other variants identified by genome-wide association studies of prostate cancer, we shall be better poised to develop the appropriate panel of markers to improve prevention and diagnosis.