Abstract

Single nucleotide polymorphisms (SNPs) in TLR genes may serve as a crucial marker for early susceptibility of various cancers including cervical cancer. The present study was therefore designed to ascertain the role of TLR4 and TLR9 SNPs and haplotypes to hrHPV infection and cervical cancer susceptibility. The study included 110 cervical cancer biopsies and 141 cervical smears from age-matched healthy controls of Gujarati ethnicity of Western India. hrHPV 16 and 18 were detected using Real-time PCR. Eight SNPs, four each in TLR4 and TLR9 were analyzed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism and Allele-Specific PCR. HPV 16 and 18 were detected in 68% cervical cancer cases. TLR4 rs4986790, rs1927911 and TLR9 rs187084 showed association with HPV 16/18 infection. CC and CT genotypes of TLR4 rs11536889 and rs1927911 respectively, and TC, CC genotypes of TLR9 rs187084, as well as minor alleles of TLR4 rs4986790 and TLR9 rs187084, were associated with the increased risk of cervical cancer. Stage-wise analysis revealed TLR9 rs187084 and rs352140 to be associated with early-stage cancer. TLR4 haplotype GTAC and TLR9 haplotype GATC were associated with the increased risk of cervical cancer while TLR4 haplotype GCAG was associated with the decreased risk. TLR4 haplotype GCAG and TLR9 haplotype GATC showed association with increased susceptibility to hrHPV infection. In conclusion, the present study revealed association of TLR4 and TLR9 polymorphisms and haplotypes with hrHPV infection and cervical cancer risk. Further evaluation of a larger sample size covering diverse ethnic populations globally is warranted.

Highlights

  • Single nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) genes may serve as a crucial marker for early susceptibility of various cancers including cervical cancer

  • Persistent high-risk HPV (hrHPV) infection has become a well-established cause of cervical carcinogenesis, not all women infected with Human papillomavirus (HPV) develop cervical cancer, whereas women without HPV infection develop cervical cancer[9]

  • The influence of TLR polymorphisms is gradually increasing in the field of biomarkers study in various diseases including cancer[10]

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Summary

Introduction

Single nucleotide polymorphisms (SNPs) in TLR genes may serve as a crucial marker for early susceptibility of various cancers including cervical cancer. The present study was designed to ascertain the role of TLR4 and TLR9 SNPs and haplotypes to hrHPV infection and cervical cancer susceptibility. The present study revealed association of TLR4 and TLR9 polymorphisms and haplotypes with hrHPV infection and cervical cancer risk. This indicates the crucial role being played by variability in the host genetic factors, affecting women’s susceptibility to HPV infection and cervical cancer One such factor is pathogen recognition receptors of the innate immune system, where Toll-like receptors (TLRs) have been identified as a key component playing a crucial role in the pathophysiology of varied human diseases, including cancer[10]. TLRs after binding to exogenous microbial or endogenous-tissue injury generated ligands activate transcription factors via adaptor protein myeloid differentiation factor 88 (MyD88) or MyD88 adaptor-like/Toll-interleukin 1 receptor domain–containing adaptor protein (Mal/TIRAP) leading to cytokines production and activation of adaptive immune response[12]

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