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Background: Chronic infection with hepatitis B (HBV) and C virus (HCV) is linked with a pro-inflammatory state, predisposing to cirrhosis and liver cancer, particularly hepatocellular carcinoma (HCC). A role for Toll-like receptor (TLR) signalling in hepatocarcinogenesis was recently documented. We hypothesised a link TLR3 and TLR4 polymorphisms and HCC, as surrogates for the significance of TLR signalling in the promotion and initiation of HCC., Materials and Methods: We recruited 174 HCV-infected patients, 100 HBV-infected patients and 360 healthy control subjects. TLR3 (rs3775290) and TLR4 (rs4986790) genotyping was done by PCR-restriction fragment length polymorphisms (PCR-RFLP), LFTs and AFP by standard routine techniques. Liver fibrosis was assessed clinically by the Fibrotest and Actitest., Result: The TLR3 rs3775290 minor T genotype was linked with increased risk of chronic HBV (P = 0.05) and HCV (P = 0.031) infection. The TLR4 rs4986790 minor G genotype was linked with significantly increased risk for HBV/HCV chronic infection (P < 0.001). Subgroups analyses indicated decreased risk of HBV-related HCC in relation to TLR3 rs3775290 CC/CT genotype (P = 0.022), with increased risk ascribed to the minor (T) allele (P = 0.04). Likewise, TLR4 rs4985790 minor (GG) genotype was positively associated with HBV-linked HCC (P < 0.001). Furthermore, a link between TLR3 TT (P < 0.001) andTLR4 GG (P = 0.04) minor genotypes was noted in relation to increased risk of HCV-related disease., Conclusion: TLR3 and TLR4 polymorphisms are promising biomarkers of liver cirrhosis and cancer associated with HBV and HCV infection.

Accumulative epidemiological evidence suggests that polymorphisms of Toll-like receptors signaling pathway elucidated the cellular and molecular mechanisms of human diseases whose gaining a primordial importance. The aim of our study is to identify the role of TLR 2 (-196 to -174 del), TLR 3 (1377 C>T), TLR 4 (Asp299Gly) and TLR 9 (G2848A) gene polymorphisms with the evolution of cervical cancer in Tunisian women. Blood samples were collected from histopathologically confirmed patients with cervical cancer and unrelated healthy female controls of similar ethnicity. Genotyping of the analyzed polymorphisms were done using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism. For the TLR 2, Ins/Ins genotype is a protector factor [p = 0.006; OR: 0.35(0.16-0.73)] and the dominant genotype of TLR 3 increased the risk of CC in stage (III+IV); C/C versus C/T [p = 0.033; OR: 2.03(1.00-4.13)] and C/C versus C/T+T/T [p = 0.036; OR: 1.93(1.00-3.74)]. For TLR 4, the dominant genotype Asp/Asp is implicated in the occurrence of CC in stage (I+II) [p = 0.000; OR: 4.55(1.58-13.06)], [p = 0.001; OR: 3.49(1.44-8.45)] and in stage (III+IV) [p = 0.038; OR: 3.77(0.87-16.29)], [p = 0.007; OR: 5.21(1.65-16.46)] and the major allele Asp is a risk factor for the development of tumor in stage (I+II). The TLR2 Ins/Del genotype is associated with tumor evolution to stage (III+IV) [p = 0.003; OR: 3.00 (1.22-7.35)] and the genotypes Gly/Gly and Asp/Gly+Gly/Gly and Gly allele of TLR 4 are implicated in tumor evolution to the advanced stages. Further, TLR 2, TLR 3, TLR 4 and TLR 9 gene polymorphisms are implicated in the modulation of CC risk due to tobacco usage and statue of menopause among cases. Our study suggests a relationship between the incidence of the TLR2, TLR 3, TLR 4 and TLR9 mutations and the clinical progression of CC according to the FIGO classification. However, future studies with different demographic and clinical characteristics in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in cervical cancer etiology in women worldwide.

Previous studies underscored the importance of genetic factors in the pathogenesis of certain cancers, including cervical cancer. Epidemiological evidence supports an association between specific polymorphisms of Toll-like receptors (TLR) with several human pathological states, including cervical cancer. The aim of this study was to investigate the link between specific gene variants in TLR2 (-196 to -174 del), TLR3 (c.1377 C>T), TLR4 (Asp299Gly), and TLR9 (2848 G>A) and susceptibility to cervical cancer in Tunisian women. Study subjects comprised 122 women with histopathologically-confirmed cervical cancer, and 260 unrelated age- and ethnically-matched healthy females, who served as controls. TLR genotyping was done using PCR-restriction fragment length polymorphism. The C/C genotype of TLR3 (c.1377 C>T) is associated with cervical cancer susceptibility (OR: 1.71, CI: 1.08-2.70). For TLR4 (Asp299Gly), the Asp/Asp genotype and the Asp allele were associated with higher risk of developing cervical cancer (OR: 4.95, CI: 1.97-13.22) and (OR: 5.17, CI: 2.11-13.50) respectively. We demonstrated no association between the TLR2 (-196 to -174 del) and the TLR 9 (2848 G>A) polymorphisms and the susceptibility of cervical cancer among Tunisian women. However, the C/C genotype for the TLR3 (c.1377 C>T) polymorphism and the Asp/Asp genotype and the Asp allele for (Asp299Gly) TLR4 polymorphism were found to be associated with a higher risk of cervical cancer.