Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility

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 Realtime 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. With respect to gender-specific cancers, cervical cancer is the next major cause of global cancer deaths among women, after the cancer of the breast, wherein India accounts for almost one-fourth of total cervical cancer-related mortalities 1. Human papillomavirus (HPV) infection is considered as the most vital event in the development and progression of cervical cancer, as the HPV DNA has been detected in almost all of the cervical tumors globally 2. With more than 200 HPV types known till date,

Risk of HPV-related extra-cervical cancers in women treated for cervical intraepithelial neoplasia

“…The correlation between anogenital tumour or pretumour lesions and HPV infection has been well described [18]. There is general consensus in stating that patients treated for high grade CIN or cervical cancer are at increased risk of invasive neoplasia and our study confirms this trend [5][6][7][8][9][10][11][12][13][14]16].…”

“…Host immunoresponse influence the effectiveness of viral clearance: primary immunodeficiency disorders but also polymorphisms in genes such as TLRs (Toll-Like receptors) and NF-kB networks are associated with higher risk of lesions [18]. Also secondary immunodeficiencies either infection-related (HIV) or iatrogenic (chemotherapy or biological drugs) elevate the risk of HPV related malignancies [4].…”

Cervical cancer in low and middle‑income countries (Review)

“…A previous meta-analysis conducted by Yang et al (78) identified an association between TLR gene polymorphisms and the risk of cervical cancer. The results revealed that white populations carrying the C allele of the TLR 9 1486 T/C gene polymorphism and the A allele of the TLR 9 G2848A gene polymorphism were significantly associated with an increased risk of developing cervical cancer (78,79). TLR 9 has been previously reported to promote cervical intraepithelial neoplasia (CIN) progression in women from Tunisia (80).…”

Role of Toll-Like Receptor (TLR)-Signaling in Cancer Progression and Treatment

“…A number of genetic changes like single nucleotide polymorphisms (SNPs) within the TLR genes has been reported in humans which can influence receptor binding and function, that ultimately influences the risk for the inflammatory diseases as well as cancers [21]. Although there have been numerous studies reporting the impact of polymorphisms on TLR function and disease development, there is still a lot of contradiction in terms of outcomes [22].…”

“…All TLRs except TLR3, which exclusively uses the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway, use MYD88 as the downstream adapter protein that activate the classical/canonical inflammatory signaling pathway [26][27][28][29]. After activation with their specific ligands, TLRs recruit MYD88, leading to subsequent activation of three main transcription factors: interferonregulatory factors (IRF3, IRF5 and IRF7), NF-kB, MAPK and AP1 [21][22][23][24][25][27][28][29][30][31][32]. Subsequently, it promote the transcription of cytokines such as TNF-α, IL-6 and IL-1, chemokines and interferons which are key mediators of inflammation [30].…”