Genetic variation in the TLR and NF‐κB pathways and cervical and vulvar cancer risk: A population‐based case–control study

Abstract

Genital infection with the oncogenic human papillomavirus (HPV) is the necessary cause of cervical cancer and of a large fraction of vulvar cancers. The toll-like receptor (TLR) and the nuclear factor κB (NF-κB) signaling pathways have been implicated in inflammation, autoimmune disease and cancer, but whether common nucleotide variation in these pathways is associated with the risk of cervical and vulvar cancers has received little study. Using data from a population-based case-control study of cervical and vulvar cancers, we genotyped 205 single nucleotide polymorphisms (SNPs) in and around 32 candidate gene regions within these pathways. Gene-based analyses were employed to estimate the associations between individual gene regions and the risk of cervical and vulvar cancers. Odds ratio (OR) and 95% confidence intervals (CI) were calculated to assess the risk of cervical and vulvar cancers for each SNP. P-values were adjusted for multiple testing. A total of 876 cervical cancer cases, 517 vulvar cancer cases and 1,100 controls were included in the analysis. The TNF region was significantly associated with the risks of cervical cancer (gene-based P-value: 2.0×10−4) and vulvar cancer (gene-based P-value: 1.0×10−4). The rare allele (A) of SNP rs2239704 in the 5′ UTR of the LTA gene was significantly associated with increased risks of cervical cancer (OR=1.31, 95% CI: 1.15–1.50; adjusted P-value: 0.013) and vulvar cancer (OR=1.51, 95% CI: 1.30–1.75; adjusted P-value: 1.9×10−5). These findings add to the evidence of the importance of the immune system in the etiology of cervical and vulvar cancers.

Differential expression of TLR3 and TLR4 in keratocystic odontogenic tumor (KCOT): A comparative immunohistochemical study in primary, recurrent, and nevoid basal cell carcinoma syndrome (NBCCS)–associated lesions

“…DAMPs can be released from cells that have been affected by various stimuli and have entered a potentially neoplastic phase, as well as from cells that have undergone malignant transformation. On these premises, a large number of studies have investigated the role of TLRs in the pathogenesis of a range of malignant neoplasms (Bodelon et al, 2014;Rich et al, 2014).…”

Expression of Toll-like Receptor 9 Increases with Progression of Cervical Neoplasia in Tunisian Women - A Comparative Analysis of Condyloma, Cervical Intraepithelial Neoplasia and Invasive Carcinoma

“…The complicated interaction between tumor cells, immune cells pathogen-associated molecular patterns in the tumor microenvironment could promote either tumor progression or apoptosis and cancer regression. The reasons for those discrepancies are not clear but genetic variations of TLR9 pathway through a polymorphism in some TLR9 regions is now under question (Pandey et al, 2011;Roszak et al, 2012;Chen et al, 2012;Oliveira et al, 2013;Lai et al, 2013;Bodelon et al, 2014) and it seems now likely to talk about cancer susceptibility and TLR9 polymorphism (Chen et al, 2012;Dai et al, 2014). Our results suggest that TLR9 may play a role in progression of cervical neoplasia in Tunisian patient and could represent a useful biomarker for malignant transformation of cervical cells.…”

“…Most of the previous reports have focused on their expression and function in cells of the immune system like B-lymphocytes and plasmacytoid dendritic cells. Current works are focusing on their association with cancers (Domingos-Pereira et al, 2013;Bodelon et al, 2014) and the use of vaccine with TLR agonist or antagonist in cervical cancer is now undergoing extensive investigations (Geller et al, 2010;Mai et al, 2013;Sajadian et al, 2014). Several previous works have shown that TLR9 signaling promotes tumor growth, survival and immune evasion in CC as in many other cancer types, such as gastric cancer (Schmausser et al, 2005), prostatic cancer (GonzalezReyes et al, 2011) breast cancer (Bhattacharya and Yusuf, 2012), lung cancer (Ren et al, 2007), glioma , and oesophageal squamous cell carcinoma (Sheyhidin et al, 2011).…”

“…Several previous works have shown that TLR9 signaling promotes tumor growth, survival and immune evasion in CC as in many other cancer types, such as gastric cancer (Schmausser et al, 2005), prostatic cancer (GonzalezReyes et al, 2011) breast cancer (Bhattacharya and Yusuf, 2012), lung cancer (Ren et al, 2007), glioma , and oesophageal squamous cell carcinoma (Sheyhidin et al, 2011). But it has also been suggested to have anti-tumor activities (Chang et al, 2014) and whether TLR9 promotes or suppress cancer development remains under discussion, leading to investigations about TLR polymorphism and genetic variations of TLR pathway (Oliveira et al, 2013;Bodelon et al,2014). The present study aims to evaluate the expression levels of TLR9 on Tunisian cervical samples in gradual stages of CINs and ISCC using normal cervical tissues and condyloma as control cases.…”

Metastasis-Associated in Colon Cancer-1 Associates With Poor Prognosis and Promotes Cell Invasion and Angiogenesis in Human Cervical Cancer

“…Nuclear factor κB signal transduction cascade, required for angiogenesis, was frequently involved in tumor progression and dissemination 35. Compelling evidence has indicated that activated NF-κB is associated with the initiation and progression of cervical cancer 36–38. Nuclear factor κB is constitutively activated in high-grade and more invasive histologic grades of cervical cancer 39.…”