Gene Summary

Gene:TLR6; toll like receptor 6
Aliases: CD286
Summary:The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor functionally interacts with toll-like receptor 2 to mediate cellular response to bacterial lipoproteins. A Ser249Pro polymorphism in the extracellular domain of the encoded protein may be associated with an increased of asthma is some populations.[provided by RefSeq, Jan 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:toll-like receptor 6
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (27)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Oligonucleotide Array Sequence Analysis
  • Up-Regulation
  • Immunity
  • Multigene Family
  • Breast Cancer
  • Sweden
  • Linkage Disequilibrium
  • Cervical Cancer
  • Toll-Like Receptor 2
  • Chromosome 4
  • Genetic Variation
  • Signal Transduction
  • Tumor Burden
  • Single Nucleotide Polymorphism
  • Staging
  • Genetic Association Studies
  • Signal Transducing Adaptor Proteins
  • Cancer DNA
  • Support Vector Machine
  • Immunohistochemistry
  • Risk Factors
  • Prostate Cancer
  • Alleles
  • Toll-Like Receptor 10
  • Inflammation
  • Young Adult
  • Haplotypes
  • Genotype
  • Cancer Gene Expression Regulation
  • Case-Control Studies
  • Genome-Wide Association Study
  • Toll-Like Receptors
  • African Americans
  • Genetic Predisposition
  • Neoplasm Proteins
  • Toll-Like Receptor 1
  • Toll-Like Receptor 6
  • Polymorphism
  • Toll-Like Receptor 4
  • Translocation
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TLR6 (cancer-related)

Semlali A, Almutairi M, Rouabhia M, et al.
Novel sequence variants in the TLR6 gene associated with advanced breast cancer risk in the Saudi Arabian population.
PLoS One. 2018; 13(11):e0203376 [PubMed] Free Access to Full Article Related Publications
Herein, we evaluated the association of the Toll-like receptor 6 (TLR6) single nucleotide polymorphisms (SNPs) rs3796508 (Val327Met) and rs5743810 (Ser249Pro) with breast cancer (BC) susceptibility in Saudi Arabian women, using in silico analysis. We found no significant differences in genotypic and allelic frequencies for rs3796508 between the BC patients (n = 127) and healthy individuals (n = 116). However, 86% of the BC patients, versus 98% of the healthy controls, carried the rs5743810 Pro allele (OR = 0.103, CI = 0.036-0.293, P = 0.00001). Advanced analysis based on the comparison of the estrogen receptor (ER)-positive and -negative patients with the healthy controls indicated a significant association between rs5743810 allelic frequency and BC risk protection (OR = 0.100, CI = 0.034-0.297, P = 0.00001 for ER+ BC cases; OR = 0.102, CI = 0.033-0.318, P = 0.00001 for ER-BC cases). Furthermore, rs5743810 was associated with BC risk protection at either above or below 48 years of age at diagnosis (OR = 0.101, CI = 0.022-0.455, P = 0.00037 for age ≤48 years; OR = 0.120, CI = 0.028-0.519, P = 0.00087 for age >48 years). Such associations were not found for rs3796508. In silico analysis indicated that these SNPs had neutral effects within the TLR6 structure, confirming the protective role of rs5743810. Our findings therefore suggest a strong association between rs5743810 and protection against BC risk in Saudi Arabian women. Importantly, the rs5743810 Pro allele could be a potential BC diagnostic biomarker in this ethnic population.

Moretti IF, Franco DG, de Almeida Galatro TF, et al.
Plasmatic membrane toll-like receptor expressions in human astrocytomas.
PLoS One. 2018; 13(6):e0199211 [PubMed] Free Access to Full Article Related Publications
Toll-like receptors (TLRs) are the first to identify disturbances in the immune system, recognizing pathogens such as bacteria, fungi, and viruses. Since the inflammation process plays an important role in several diseases, TLRs have been considered potential therapeutic targets, including treatment for cancer. However, TLRs' role in cancer remains ambiguous. This study aims to analyze the expression levels of plasmatic cell membrane TLRs (TLR1, TLR2, TLR4, TLR5, and TLR6) in human astrocytomas the most prevalent tumors of CNS different grades (II-IV). We demonstrated that TLR expressions were higher in astrocytoma samples compared to non-neoplastic brain tissue. The gene and protein expressions were observed in GBM cell lines U87MG and A172, proving their presence in the tumor cells. Associated expressions between the known heterodimers TLR1-TLR2 were found in all astrocytoma grades. In GBMs, the mesenchymal subtype showed higher levels of TLR expressions in relation to classical and proneural subtypes. A strong association of TLRs with the activation of cell cycle process and signaling through canonical, inflammasome and ripoptosome pathways was observed by in silico analysis, further highlighting TLRs as interesting targets for cancer treatment.

Hong CC, Sucheston-Campbell LE, Liu S, et al.
Genetic Variants in Immune-Related Pathways and Breast Cancer Risk in African American Women in the AMBER Consortium.
Cancer Epidemiol Biomarkers Prev. 2018; 27(3):321-330 [PubMed] Free Access to Full Article Related Publications

Gillman AS, Gardiner CK, Koljack CE, Bryan AD
Body mass index, diet, and exercise: testing possible linkages to breast cancer risk via DNA methylation.
Breast Cancer Res Treat. 2018; 168(1):241-248 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To examine DNA methylation as a mechanism linking diet, physical activity, weight status, and breast cancer risk.
METHODS: Insufficiently active women of varying weight status, without a history of cancer, completed a maximal exercise test, clinical measurement of height and weight, and a dietary intake measure. They also provided blood samples, which were analyzed to ascertain average methylation of candidate genes related to breast cancer (BRCA1, RUNX3, GALNT9, and PAX6) and inflammation (TLR4 and TLR6).
RESULTS: Elevated weight status (r = - .18, p < .05) and poorer aerobic fitness (r = .24, p < .01) were each associated with decreased methylation of inflammation genes. Methylation of inflammation genes statistically mediated the relationship between weight status and cancer gene methylation (standardized indirect effect = .12, p < .05) as well as between cardiorespiratory fitness and cancer gene methylation (standardized indirect effect = - .172, p < .01). However, recent dietary behavior was not associated with methylation of either inflammation or cancer genes.
CONCLUSIONS: Both weight status and cardiovascular fitness are associated with methylation of genes associated with both inflammation and cancer. Methylation of inflammatory genes might serve as a mechanistic link between lifestyle factors and methylation changes in genes that increase risk for breast cancer.

Okazaki S, Loupakis F, Stintzing S, et al.
Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab.
Mol Cancer Ther. 2016; 15(7):1740-5 [PubMed] Free Access to Full Article Related Publications
The purpose of this study was to evaluate the clinical significance of single-nucleotide polymorphisms in TLR1, TLR2, TLR6, and TAK1 in patients with metastatic colorectal cancer (mCRC). We genotyped 9 SNPs of TLR1, TLR2, TLR6, and TAK1 in mCRC patients treated with first-line FOLFIRI (combination therapy of irinotecan, 5-fluorouracil, and folinic acid) plus bevacizumab, using a discovery cohort (TRIBE trial, n = 228) and a validation cohort (FIRE-3 trial, n = 297), and analyzed for the association with response rate (RR), progression-free survival (PFS), and overall survival (OS). There was a significant association of TLR1 rs5743618 (T1805G) with the clinical outcome. In the TRIBE cohort, a homozygous wild-type genotype (T/T) associated with a significantly lower RR compared with variant T/G and G/G genotypes (43% vs. 62%, P = 0.025), and this observation was validated in the FIRE-3 cohort (46% vs. 65%, P = 0.021). In addition, those patients with the T/T genotype had significantly worse PFS (median, 8.2 vs. 10.5 months; HR, 1.57; 95% CI, 1.09-2.28, P = 0.014) and OS (median: 19.9 vs. 27.9 months; HR, 1.63; 95% CI, 1.14-2.35, P = 0.007), compared with those with other genotypes in the TRIBE cohort. These differences remained statistically significant in multivariate analysis. Our data suggest that TLR1 rs5743618 could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC. Mol Cancer Ther; 15(7); 1740-5. ©2016 AACR.

Shelburne SA, Ajami NJ, Chibucos MC, et al.
Implementation of a Pan-Genomic Approach to Investigate Holobiont-Infecting Microbe Interaction: A Case Report of a Leukemic Patient with Invasive Mucormycosis.
PLoS One. 2015; 10(11):e0139851 [PubMed] Free Access to Full Article Related Publications
Disease can be conceptualized as the result of interactions between infecting microbe and holobiont, the combination of a host and its microbial communities. It is likely that genomic variation in the host, infecting microbe, and commensal microbiota are key determinants of infectious disease clinical outcomes. However, until recently, simultaneous, multiomic investigation of infecting microbe and holobiont components has rarely been explored. Herein, we characterized the infecting microbe, host, micro- and mycobiomes leading up to infection onset in a leukemia patient that developed invasive mucormycosis. We discovered that the patient was infected with a strain of the recently described Mucor velutinosus species which we determined was hypervirulent in a Drosophila challenge model and has a predisposition for skin dissemination. After completing the infecting M. velutinosus genome and genomes from four other Mucor species, comparative pathogenomics was performed and assisted in identifying 66 M. velutinosus-specific putatively secreted proteins, including multiple novel secreted aspartyl proteinases which may contribute to the unique clinical presentation of skin dissemination. Whole exome sequencing of the patient revealed multiple non-synonymous polymorphisms in genes critical to control of fungal proliferation, such as TLR6 and PTX3. Moreover, the patient had a non-synonymous polymorphism in the NOD2 gene and a missense mutation in FUT2, which have been linked to microbial dysbiosis and microbiome diversity maintenance during physiologic stress, respectively. In concert with host genetic polymorphism data, the micro- and mycobiome analyses revealed that the infection developed amid a dysbiotic microbiome with low α-diversity, dominated by staphylococci. Additionally, longitudinal mycobiome data showed that M. velutinosus DNA was detectable in oral samples preceding disease onset. Our genome-level study of the host-infecting microbe-commensal triad extends the concept of personalized genomic medicine to the holobiont-infecting microbe interface thereby offering novel opportunities for using synergistic genetic methods to increase understanding of infectious diseases pathogenesis and clinical outcomes.

Dorman SN, Baranova K, Knoll JH, et al.
Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning.
Mol Oncol. 2016; 10(1):85-100 [PubMed] Free Access to Full Article Related Publications
Increasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients. Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n = 31 genes) or gemcitabine (n = 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression were informative for gemcitabine. The factors were combined using support vector machines (SVM). Expression of 15 genes (ABCC10, BCL2, BCL2L1, BIRC5, BMF, FGF2, FN1, MAP4, MAPT, NFKB2, SLCO1B3, TLR6, TMEM243, TWIST1, and CSAG2) predicted cell line sensitivity to paclitaxel with 82% accuracy. Copy number profiles of 3 genes (ABCC10, NT5C, TYMS) together with expression of 7 genes (ABCB1, ABCC10, CMPK1, DCTD, NME1, RRM1, RRM2B), predicted gemcitabine response with 85% accuracy. Expression and copy number studies of two independent sets of patients with known responses were then analyzed with these models. These included tumor blocks from 21 patients that were treated with both paclitaxel and gemcitabine, and 319 patients on paclitaxel and anthracycline therapy. A new paclitaxel SVM was derived from an 11-gene subset since data for 4 of the original genes was unavailable. The accuracy of this SVM was similar in cell lines and tumor blocks (70-71%). The gemcitabine SVM exhibited 62% prediction accuracy for the tumor blocks due to the presence of samples with poor nucleic acid integrity. Nevertheless, the paclitaxel SVM predicted sensitivity in 84% of patients with no or minimal residual disease.

Akhter A, Street L, Ghosh S, et al.
Concomitant high expression of Toll-like receptor (TLR) and B-cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma.
Hematol Oncol. 2017; 35(1):79-86 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B-cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll-like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCR

Fonte E, Agathangelidis A, Reverberi D, et al.
Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation.
Haematologica. 2015; 100(11):1460-8 [PubMed] Free Access to Full Article Related Publications
Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLRs. We aimed at characterizing the expression pattern of TLRs in splenic marginal zone lymphoma cells and their functional impact on the activation, proliferation and viability of malignant cells in vitro. Cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9 and TLR10 mRNA; TLR2 and TLR4 showed a low, variable pattern of expression among patients whereas TLR3 and TLR5 mRNAs were undetectable; mRNA specific for TLR signaling molecules and adapters was also expressed. At the protein level, TLR1, TLR6, TLR7, TLR9 and TLR10 were detected. Stimulation of TLR1/2, TLR2/6 and TLR9 with their respective ligands triggered the activation of IRAK kinases, MAPK and NF-κB signaling pathways, and the induction of CD86 and CD25 activation molecules, although in a heterogeneous manner among different patient samples. TLR-induced activation and cell viability were also inhibited by a specific IRAK1/4 inhibitor, thus strongly supporting the specific role of TLR signaling in these processes. Furthermore, TLR2/6 and TLR9 stimulation also significantly increased cell proliferation. In conclusion, we demonstrate that splenic marginal zone lymphoma cells are equipped with functional TLR and signaling molecules and that the stimulation of TLR1/2, TLR2/6 and TLR9 may play a role in regulating disease pathobiology, likely promoting the expansion of the neoplastic clone.

Aggarwal R, Misra S, Guleria C, et al.
Characterization of Toll-like receptor transcriptome in squamous cell carcinoma of cervix: A case-control study.
Gynecol Oncol. 2015; 138(2):358-62 [PubMed] Related Publications
OBJECTIVE: Human papillomavirus (HPV) is a proven etiological agent for cervical cancer However, not all HPV infections result in cervical cancer. The mechanisms of host immune system to prevent/control HPV infection remain poorly understood. Toll-like receptors (TLRs) are a system of innate immune defense. HPV has been demonstrated to modulate TLR expression and interfere in TLR signaling pathways, leading to persistent viral infection and carcinogenesis. The aim was to study the relative gene expression of TLRs in cervical squamous cell carcinoma (SCC).
METHODS: Gene expression profile of TLRs 1 to 9 was examined in 30 cervical SCCs and an equal number of normal cervical tissue samples using a PCR array platform. Gene expression studies for TLRs 3 and 7 were validated by western blotting.
RESULTS: HPV was detected in all cases and in none of the controls (p<0.0001). HPV16 was the preponderant (83.3%) subtype. A significant downregulation in the relative gene expression of TLR3 (p<0.0001), TLR4 (p<0.0005) and TLR5 (p<0.0001) was observed in cases. A significant upregulation for TLR1 was observed (p=0.006). Although TLRs 2, 7, 8 and 9 were upregulated and TLR6 was downregulated, it was not significant. The western blot performed with antibodies against TLRs 3 and 7 confirmed the findings of the gene expression studies.
CONCLUSIONS: A significant downregulation in the gene expression of TLRs 3, 4 and 5 and upregulation of TLR1 was observed in cervical SCC as compared to controls. Study results evoke the proposition for investigating TLRs 3, 4 and 5 agonists for therapeutic exploration.

Cotterchio M, Lowcock E, Bider-Canfield Z, et al.
Association between Variants in Atopy-Related Immunologic Candidate Genes and Pancreatic Cancer Risk.
PLoS One. 2015; 10(5):e0125273 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Many epidemiology studies report that atopic conditions such as allergies are associated with reduced pancreas cancer risk. The reason for this relationship is not yet understood. This is the first study to comprehensively evaluate the association between variants in atopy-related candidate genes and pancreatic cancer risk.
METHODS: A population-based case-control study of pancreas cancer cases diagnosed during 2011-2012 (via Ontario Cancer Registry), and controls recruited using random digit dialing utilized DNA from 179 cases and 566 controls. Following an exhaustive literature review, SNPs in 180 candidate genes were pre-screened using dbGaP pancreas cancer GWAS data; 147 SNPs in 56 allergy-related immunologic genes were retained and genotyped. Logistic regression was used to estimate age-adjusted odd ratio (AOR) for each variant and false discovery rate was used to adjust Wald p-values for multiple testing. Subsequently, a risk allele score was derived based on statistically significant variants.
RESULTS: 18 SNPs in 14 candidate genes (CSF2, DENND1B, DPP10, FLG, IL13, IL13RA2, LRP1B, NOD1, NPSR1, ORMDL3, RORA, STAT4, TLR6, TRA) were significantly associated with pancreas cancer risk. After adjustment for multiple comparisons, two LRP1B SNPs remained statistically significant; for example, LRP1B rs1449477 (AA vs. CC: AOR=0.37, 95% CI: 0.22-0.62; p (adjusted)=0.04). Furthermore, the risk allele score was associated with a significant reduction in pancreas cancer risk (p=0.0007).
CONCLUSIONS: Preliminary findings suggest certain atopy-related variants may be associated with pancreas cancer risk. Further studies are needed to replicate this, and to elucidate the biology behind the growing body of epidemiologic evidence suggesting allergies may reduce pancreatic cancer risk.

Borkowski J, Li L, Steinmann U, et al.
Neisseria meningitidis elicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model.
J Neuroinflammation. 2014; 11:163 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The human-specific, Gram-negative bacterium Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis worldwide. The blood-cerebrospinal fluid barrier (BCSFB), which is constituted by the epithelial cells of the choroid plexus (CP), has been suggested as one of the potential entry sites of Nm into the CSF and can contribute to the inflammatory response during infectious diseases of the brain. Toll-like receptors (TLRs) are involved in mediating signal transduction caused by the pathogens.
METHODS: Using a recently established in vitro model of the human BCSFB based on human malignant CP papilloma (HIBCPP) cells we investigated the cellular response of HIBCPP cells challenged with the meningitis-causing Nm strain, MC58, employing transcriptome and RT-PCR analysis, cytokine bead array, and enzyme-linked immunosorbent assay (ELISA). In comparison, we analyzed the answer to the closely related unencapsulated carrier isolate Nm α14. The presence of TLRs in HIBCPP and their role during signal transduction caused by Nm was studied by RT-PCR and the use of specific agonists and mutant bacteria.
RESULTS: We observed a stronger transcriptional response after infection with strain MC58, in particular with its capsule-deficient mutant MC58siaD-, which correlated with bacterial invasion levels. Expression evaluation and Gene Set Enrichment Analysis pointed to a NFκB-mediated pro-inflammatory immune response involving up-regulation of the transcription factor IκBζ. Infected cells secreted significant levels of pro-inflammatory chemokines and cytokines, including, among others, IL8, CXCL1-3, and the IκBζ target gene product IL6. The expression profile of pattern recognition receptors in HIBCPP cells and the response to specific agonists indicates that TLR2/TLR6, rather than TLR4 or TLR2/TLR1, is involved in the cellular reaction following Nm infection.
CONCLUSIONS: Our data show that Nm can initiate a pro-inflammatory response in human CP epithelial cells probably involving TLR2/TLR6 signaling and the transcriptional regulator IκBζ.

Wang J, Hu G, Lin Z, et al.
Characteristic and functional analysis of a newly established porcine small intestinal epithelial cell line.
PLoS One. 2014; 9(10):e110916 [PubMed] Free Access to Full Article Related Publications
The mucosal surface of intestine is continuously exposed to both potential pathogens and beneficial commensal microorganisms. Recent findings suggest that intestinal epithelial cells, which once considered as a simple physical barrier, are a crucial cell lineage necessary for maintaining intestinal immune homeostasis. Therefore, establishing a stable and reliable intestinal epithelial cell line for future research on the mucosal immune system is necessary. In the present study, we established a porcine intestinal epithelial cell line (ZYM-SIEC02) by introducing the human telomerase reverse transcriptase (hTERT) gene into small intestinal epithelial cells derived from a neonatal, unsuckled piglet. Morphological analysis revealed a homogeneous cobblestone-like morphology of the epithelial cell sheets. Ultrastructural indicated the presence of microvilli, tight junctions, and a glandular configuration typical of the small intestine. Furthermore, ZYM-SIEC02 cells expressed epithelial cell-specific markers including cytokeratin 18, pan-cytokeratin, sucrase-isomaltase, E-cadherin and ZO-1. Immortalized ZYM-SIEC02 cells remained diploid and were not transformed. In addition, we also examined the host cell response to Salmonella and LPS and verified the enhanced expression of mRNAs encoding IL-8 and TNF-α by infection with Salmonella enterica serovars Typhimurium (S. Typhimurium). Results showed that IL-8 protein expression were upregulated following Salmonella invasion. TLR4, TLR6 and IL-6 mRNA expression were upregulated following stimulation with LPS, ZYM-SIEC02 cells were hyporeponsive to LPS with respect to IL-8 mRNA expression and secretion. TNFα mRNA levels were significantly decreased after LPS stimulation and TNF-α secretion were not detected challenged with S. Typhimurium neither nor LPS. Taken together, these findings demonstrate that ZYM-SIEC02 cells retained the morphological and functional characteristics typical of primary swine intestinal epithelial cells and thus provide a relevant in vitro model system for future studies on porcine small intestinal pathogen-host cell interactions.

Martínez-Trillos A, Pinyol M, Navarro A, et al.
Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome.
Blood. 2014; 123(24):3790-6 [PubMed] Related Publications
Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.

Hope C, Ollar SJ, Heninger E, et al.
TPL2 kinase regulates the inflammatory milieu of the myeloma niche.
Blood. 2014; 123(21):3305-15 [PubMed] Free Access to Full Article Related Publications
Targeted modulation of microenvironmental regulatory pathways may be essential to control myeloma and other genetically/clonally heterogeneous cancers. Here we report that human myeloma-associated monocytes/macrophages (MAM), but not myeloma plasma cells, constitute the predominant source of interleukin-1β (IL-1β), IL-10, and tumor necrosis factor-α at diagnosis, whereas IL-6 originates from stromal cells and macrophages. To dissect MAM activation/cytokine pathways, we analyzed Toll-like receptor (TLR) expression in human myeloma CD14(+) cells. We observed coregulation of TLR2 and TLR6 expression correlating with local processing of versican, a proteoglycan TLR2/6 agonist linked to carcinoma progression. Versican has not been mechanistically implicated in myeloma pathogenesis. We hypothesized that the most readily accessible target in the versican-TLR2/6 pathway would be the mitogen-activated protein 3 (MAP3) kinase, TPL2 (Cot/MAP3K8). Ablation of Tpl2 in the genetically engineered in vivo myeloma model, Vκ*MYC, led to prolonged disease latency associated with plasma cell growth defect. Tpl2 loss abrogated the "inflammatory switch" in MAM within nascent myeloma lesions and licensed macrophage repolarization in established tumors. MYC activation/expression in plasma cells was independent of Tpl2 activity. Pharmacologic TPL2 inhibition in human monocytes led to dose-dependent attenuation of IL-1β induction/secretion in response to TLR2 stimulation. Our results highlight a TLR2/6-dependent TPL2 pathway as novel therapeutic target acting nonautonomously through macrophages to control myeloma progression.

Chen SK, Chung CA, Cheng YC, et al.
Toll-like receptor 6 and connective tissue growth factor are significantly upregulated in mitomycin-C-treated urothelial carcinoma cells under hydrostatic pressure stimulation.
Genet Test Mol Biomarkers. 2014; 18(6):410-6 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) is the most common histologic subtype of bladder cancer. The administration of mitomycin C (MMC) into the bladder after transurethral resection of the bladder tumor (TURBT) is a common treatment strategy for preventing recurrence after surgery. We previously applied hydrostatic pressure combined with MMC in UC cells and found that hydrostatic pressure synergistically enhanced MMC-induced UC cell apoptosis through the Fas/FasL pathways. To understand the alteration of gene expressions in UC cells caused by hydrostatic pressure and MMC, oligonucleotide microarray was used to explore all the differentially expressed genes.
RESULTS: After bioinformatics analysis and gene annotation, Toll-like receptor 6 (TLR6) and connective tissue growth factor (CTGF) showed significant upregulation among altered genes, and their gene and protein expressions with each treatment of UC cells were validated by quantitative real-time PCR and immunoblotting.
CONCLUSION: Under treatment with MMC and hydrostatic pressure, UC cells showed increasing apoptosis using extrinsic pathways through upregulation of TLR6 and CTGF.

Bagheri V, Askari A, Arababadi MK, Kennedy D
Can Toll-Like Receptor (TLR) 2 be considered as a new target for immunotherapy against hepatitis B infection?
Hum Immunol. 2014; 75(6):549-54 [PubMed] Related Publications
The current literature describes pivotal mechanisms in which hepatitis B virus (HBV) induces liver diseases including inflammation, cirrhosis and hepatocellular carcinoma (HCC). It appears that differences in genetic and immunological parameters between patients and controls may be responsible for inducing the prolonged forms of the infection. Previous studies demonstrated that Toll-Like Receptors (TLRs) play key roles in viral recognition and inducing appropriate immune responses. Therefore, TLRs can be considered as key sensors for HBV recognition and subsequent induction of immune responses against this virus. It has also been shown that the TLR2 detects several microbial PAMPs either in its homodimer form or in a heterodimer with TLR1 or TLR6 and subsequently activates NF-κB in a MYD88 dependent manner. Therefore, defective TLR2 expression may result in impaired immune responses against HBV which is reported in long-term forms of hepatitis B. This review presents the recent data regarding the status and important roles played by TLR2 in HBV recognition and induction or suppression of immune responses against HBV as well as its roles in the pathogenesis of cirrhosis and HCC in prolonged hepatitis B forms.

Rogers EN, Jones DZ, Kidd NC, et al.
Toll-like receptor-associated sequence variants and prostate cancer risk among men of African descent.
Genes Immun. 2013; 14(6):347-55 [PubMed] Free Access to Full Article Related Publications
Recent advances demonstrate a relationship between chronic/recurrent inflammation and prostate cancer (PCA). Among inflammatory regulators, toll-like receptors (TLRs) have a critical role in innate immune responses. However, it remains unclear whether variant TLR genes influence PCA risk among men of African descent. Therefore, we evaluated the impact of 32 TLR-associated single-nucleotide polymorphisms (SNPs) on PCA risk among African Americans and Jamaicans. SNP profiles of 814 subjects were evaluated using Illumina's Veracode genotyping platform. Single and combined effects of SNPs in relation to PCA risk were assessed using age-adjusted logistic regression and entropy-based multifactor dimensionality reduction (MDR) models. Seven sequence variants detected in TLR6, TOLLIP (Toll-interacting protein), IRAK4 (interleukin-1 receptor-associated kinase 4) and IRF3 (interferon regulatory factor 3) were marginally related to PCA. However, none of these effects remained significant after adjusting for multiple hypothesis testing. Nevertheless, MDR modeling revealed a complex interaction between IRAK4 rs4251545 and TLR2 rs1898830 as a significant predictor of PCA risk among US men (permutation testing P-value=0.001). However, these findings require further assessment and validation.

Sahingur SE, Xia XJ, Voth SC, et al.
Increased nucleic Acid receptor expression in chronic periodontitis.
J Periodontol. 2013; 84(10):e48-57 [PubMed] Related Publications
BACKGROUND: Nucleic acid sensing has emerged as one of the important components of the immune system triggering inflammation. The aim of this study is to determine the expression of bacterial DNA sensors, including Toll-like receptor 9 (TLR-9), DNA-dependent activator of interferon-regulatory factors (DAI), and absent in melanoma 2 (AIM2) in chronic periodontitis (CP versus healthy) (H) tissues.
METHODS: Thirty-five CP and 27 H gingival biopsies were included. Real-time quantitative polymerase chain reaction was performed to determine mRNA levels of AIM2, DAI, and TLRs (TLR-1 through TLR-9). The difference in gene expression for each sensor between CP and H tissues was calculated using analysis of covariance. The Spearman test was used to determine correlations among innate receptors. The expression of TLR-9, AIM2, and DAI in gingival tissues was further confirmed using immunohistochemistry.
RESULTS: The present results reveal statistically significant upregulation of TLR-9 (P <0.006), DAI (P <0.001), and TLR-8 (P <0.01) in CP tissues compared to H sites. Although mRNA expression was not changed significantly between groups for other receptors, the present results reveal significant correlations between receptors (P <0.05), suggesting that cooperation between multiple components of the host immune system may influence the overall response. Immunohistochemistry further confirmed expression of TLR-9, AIM2, and DAI in gingival tissues.
CONCLUSIONS: This study highlights a possible role for nucleic acid receptors in periodontal inflammation. Future investigations will determine whether cytoplasmic receptors and their ligands can be targeted to improve clinical outcomes in periodontitis.

Li D, Wang X, Wu JL, et al.
Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro.
PLoS One. 2013; 8(2):e56616 [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages have been shown to promote tumor growth. They may have an obligatory function in angiogenesis, invasion, and metastasis through release of inflammatory mediators. Their presence in ovarian cancer has been correlated with poor prognosis in these patients. The human cationic antimicrobial protein-18 (hCAP18)/LL-37 was originally identified as an effector molecule of the innate immune system. It is released by innate immune cells, such as macrophages, to combat microorganisms. Previous studies have characterized the hCAP18/LL-37 as a growth factor that has been shown to promote ovarian tumor progression. However, the role hCAP18/LL-37 has in macrophage-promoted ovarian tumor development and how its expression is controlled in this context remains poorly understood. Here, we demonstrate in co-culture experiments of macrophages and ovarian cancer cells a significant increase in the in vitro proliferation and invasiveness of the tumor cells is observed. These enhanced growth and invasion properties correlated with hCAP18/LL-37 induction. HCAP18/LL-37 expression was diminished by addition of two neutralizing antibodies, TLR2 or TLR6, as well as Cyp27B1 or VDR inhibitors. Furthermore, either the TLR2 or TLR6 antibody reduced vitamin D3 signaling and tumor cell progression in vitro. Addition of Cyp27B1 or VDR inhibitors abrogated TLR2/6 activation-induced expression of hCAP18/LL-37 in macrophages. Knockdown of tumor-produced versican V1 by RNAi in these tumor cells led to a decreased induction of hCAP18/LL-37 in macrophages. Versican V1 knockdown also inhibited TLR2 and vitamin D3 signaling, as well as growth and invasiveness of these tumor cells in the in vitro co-culture. In summary, we have found that versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and subsequent vitamin D-dependent mechanisms which promote ovarian tumor progression in vitro.

Kazma R, Mefford JA, Cheng I, et al.
Association of the innate immunity and inflammation pathway with advanced prostate cancer risk.
PLoS One. 2012; 7(12):e51680 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.

Kim SK, Park HJ, Hong IK, et al.
A missense polymorphism (rs11466653, Met326Thr) of toll-like receptor 10 (TLR10) is associated with tumor size of papillary thyroid carcinoma in the Korean population.
Endocrine. 2013; 43(1):161-9 [PubMed] Related Publications
Toll-like receptors (TLRs) are important components of innate immune response. The aim of this study was to investigate whether TLR gene cluster (TLR10-TLR1-TLR6) polymorphisms are associated with the etiology of papillary thyroid carcinoma (PTC) and its clinicopathologic characteristics. We recruited 94 PTC patients and 325 control subjects. Genotypes for each SNP were determined by direct sequencing. SNPStats and SPSS 18.0 were used to evaluate odds ratios (ORs), 95 % confidence intervals (CIs), and P values. Multiple logistic regression analyzes of genetic data were performed. The missense SNP rs11466653 was associated with small tumor size (<1 cm) in PTC. The frequency of the rs11466653 T allele was higher in PTC patients with tumors <1 cm in size than in the control group (95.8 vs. 87.2 %; P = 0.021, OR = 0.30, 95 % CI = 0.11-0.83). The T allele of rs11466653 (T/C, Met326Thr) in TLR10 may be a risk factor for the development of tumors in PTC in the Korean population.

Chan M, Ji SM, Liaw CS, et al.
Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.
Breast Cancer Res Treat. 2012; 136(1):209-20 [PubMed] Related Publications
Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Bi Y, Zeng N, Chanudet E, et al.
A20 inactivation in ocular adnexal MALT lymphoma.
Haematologica. 2012; 97(6):926-30 [PubMed] Free Access to Full Article Related Publications
Recent studies showed A20 inactivation by deletion, mutation and promoter methylation in ocular adnexal mucosa-associated lymphoid tissue lymphoma. However, the incidences of A20 abnormalities and their clinical impact remain for the most part unknown. It is also unknown whether ABIN-1 and ABIN-2, the components of the A20 NF-κB inhibitor complex, are inactivated by genetic changes in ocular adnexal mucosa-associated lymphoid tissue lymphoma. A total of 105 cases were investigated for A20 mutation/deletion, ABIN-1/2 mutation, MALT1 and IGH involved translocation. Somatic mutation was seen frequently in A20 (28.6%) but rarely in ABIN-1 (1%) and ABIN-2 (1%). A20 mutations were significantly associated with A20 heterozygous deletion, and both were mutually exclusive from the MALT1 or IGH involved translocations. A20 mutation/deletion was also significantly associated with increased expression of the NF-κB target genes CCR2, TLR6 and BCL2. The cases with A20 mutation/deletion required significantly higher radiation dosages to achieve complete remission than those without these abnormalities.

Miedema KG, Tissing WJ, Te Poele EM, et al.
Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease.
Leukemia. 2012; 26(6):1203-10 [PubMed] Related Publications
Little is known about the etiology of childhood acute lymphoblastic leukemia (ALL). The presence of atopic disease has been shown to protect against developing childhood ALL. The aim of this study was to examine whether single nucleotide polymorphisms (SNPs) in innate immunity genes previously associated with atopic disease, can elucidate the inverse association between childhood ALL and atopic disease. We studied 525 children, including 192 with childhood ALL, 149 with atopic disease and 184 healthy control subjects. We compared genotype distributions of 29 SNPs in genes of TLR2, TLR4, TLR6, TLR9, TLR10 and CD14 between the three groups and corrected for multiple testing. The genotype distributions of two SNPs in the TLR6 gene, rs5743798 and rs6531666, differed significantly between children with ALL, children with atopic disease and control subjects. Particularly in children with atopic eczema, risk alleles for atopic disease were observed more often than in control subjects, and less often in children with ALL than in control subjects. These findings support the immune surveillance hypothesis as an explanation for the protective association of atopic disease on childhood ALL. Further investigation is warranted to examine in more detail the role of innate immunity in the development of childhood ALL.

Kutikhin AG
Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk.
Hum Immunol. 2011; 72(11):1095-116 [PubMed] Related Publications
Toll-like receptors (TLRs) constitute a family of receptors directly recognizing a wide spectrum of exogenous and endogenous ligands playing the key role in realization of innate and adaptive immune response, and participating in the processes of cell proliferation, survival, apoptosis, angiogenesis, tissue remodeling and repair. Polymorphisms in TLR genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. The short list of TLR polymorphisms perspective for oncogenomic investigations can include rs10008492, rs4833103, rs5743815, rs11466657, rs7696175 (TLR1-TLR6-TLR10 gene cluster); rs3804100, rs4696480, -196 - -174 del (Delta22), GT-microsatellite polymorphism (TLR2); 829A/C (TLR3); rs5743836, rs352140 (TLR9). The extended list can additionally include rs4833095 rs5743551, rs5743618 (TLR1); rs5743704, rs62323857, rs1219178642 (TLR2); rs5743305, rs3775291, rs121434431, rs5743316 (TLR3); rs5744168 (TLR5); rs179008 (TLR7); rs3764880, rs2407992 (TLR8); rs352139, rs187084, rs41308230, rs5743844 (TLR9); rs4129009 (TLR10). General reasons for discrepancies between studies are insufficiency of sample size, age/gender/BMI/ethnic/racial differences, differences in prevalence of infectious agent in case and control groups, differences in immune response caused by specific ligand, differences in stratification, methods of diagnostics of cancer or chronic inflammatory conditions, genotyping methods, and chance. Future well-designed studies on large samples should shed light on the significance of TLR polymorphisms for cancer prevention.

Arvaniti E, Ntoufa S, Papakonstantinou N, et al.
Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients.
Haematologica. 2011; 96(11):1644-52 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Signaling through the B-cell receptor appears to be a major contributor to the pathogenesis of chronic lymphocytic leukemia. Toll-like receptors bridge the innate and adaptive immune responses by acting as co-stimulatory signals for B cells. The available data on the expression of Toll-like receptors in chronic lymphocytic leukemia are limited and derive from small series of patients.
DESIGN AND METHODS: We profiled the expression of genes associated with Toll-like receptor signaling pathways in 192 cases of chronic lymphocytic leukemia and explored potential associations with molecular features of the clonotypic B-cell receptors.
RESULTS: Chronic lymphocytic leukemia cells express all Toll-like receptors expressed by normal activated B cells, with high expression of TLR7 and CD180, intermediate expression of TLR1, TLR6, TLR10 and low expression of TLR2 and TLR9. The vast majority of adaptors, effectors and members of the NFKB, JNK/p38, NF/IL6 and IRF pathways are intermediately-to-highly expressed, while inhibitors of Toll-like receptor activity are generally low-to-undetectable, indicating that the Toll-like receptor-signaling framework is competent in chronic lymphocytic leukemia. Significant differences were identified for selected genes between cases carrying mutated or unmutated IGHV genes or assigned to different subsets with stereotyped B-cell receptors. The differentially expressed molecules include receptors, NFκB/MAPK signaling molecules and final targets of the cascade.
CONCLUSIONS: The observed variations are suggestive of distinctive activation patterns of the Toll-like receptor signaling pathway in subgroups of cases of chronic lymphocytic leukemia defined by the molecular features of B-cell receptors. Additionally, they indicate that different or concomitant signals acting through receptors other than the B-cell receptor can affect the behavior of the malignant clone.

Barnholtz-Sloan JS, Shetty PB, Guan X, et al.
FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women.
Carcinogenesis. 2010; 31(8):1417-23 [PubMed] Free Access to Full Article Related Publications
Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry [odds ratios (OR) range 1.17-1.81]. Associations were observed for SNPs in FGFR2, LSP1, H19, TLR1/TLR6 and RELN for AA; FGFR2, TNRC9, H19 and MAP3K1 for Whites; FGFR2, TNRC9, Msc5A1 and chromosome 8q for women > or =50 years old and FGFR2 and TNRC9 for women <50 years old. FGFR2 haplotypes based upon rs11200014, rs2981579, rs1219648 and rs2420946 were associated with increased risk of breast cancer, including the GTGT haplotype in AAs [OR = 1.27, 95% confidence interval (CI) 1.04-1.56] and younger women of either race [OR = 1.35, 95% CI 1.02-1.78) and the ATGT haplotype in Whites (OR = 1.30, 95% CI 1.15-1.46). Recent GWAS hits for breast cancer in Europeans and Whites (i.e. women of European descent) thus showed evidence of replication among AAs and Whites in the CBCS. Several new haplotypes were associated with breast cancer in AA and younger women, particularly the FGFR2 GTGT haplotype. These results highlight the need to conduct GWAS among younger women and in a variety of racial-ethnic populations.

Hamoudi RA, Appert A, Ye H, et al.
Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism.
Leukemia. 2010; 24(8):1487-97 [PubMed] Related Publications
Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-kappaB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-kappaB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-kappaB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocation-negative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-kappaB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.

Rajaraman P, Brenner AV, Neta G, et al.
Risk of meningioma and common variation in genes related to innate immunity.
Cancer Epidemiol Biomarkers Prev. 2010; 19(5):1356-61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The etiology of meningioma, the second most common type of adult brain tumor in the United States, is largely unknown. Prior studies indicate that history of immune-related conditions may affect the risk of meningioma.
METHODS: To identify genetic markers for meningioma in genes involved with innate immunity, we conducted an exploratory association study of 101 meningioma cases and 330 frequency-matched controls of European ancestry using subjects from a hospital-based study conducted by the National Cancer Institute. We genotyped 1,407 "tag" single nucleotide polymorphisms (SNP) in 148 genetic regions chosen on the basis of an r2>0.8 and minor allele frequency of >5% in Caucasians in HapMap1. Risk of meningioma was estimated by odds ratios and 95% confidence intervals.
RESULTS: Seventeen SNPs distributed across 12 genetic regions (NFKB1 (3), FCER1G (3), CCR6 (2), VCAM1, CD14, TNFRSF18, RAC2, XDH, C1D, TLR1/TLR10/TLR6, NOS1, and DEFA5) were associated with the risk of meningioma with P<0.01. Although individual SNP tests were not significant after controlling for multiple comparisons, gene region-based tests were statistically significant (P<0.05) for TNFRSF18, NFKB1, FCER1G, CD14, C1D, CCR6, and VCAM1.
CONCLUSIONS AND IMPACT: Our results indicate that common genetic polymorphisms in innate immunity genes may be associated with risk of meningioma. Given the small sample size, replication of these results in a larger study of meningioma is needed.

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