The association of the <i>TNFα</i> gene <i>rs1800629</i> and <i>TLR3</i> gene <i>rs3775291</i> polymorphisms with cervical cancer risk and its survival outcomes

Background: Cervical cancer (CC) ranks fourth in the cancer morbidity and mortality in women. In 2022, in the Russian Federation the standardized incidence and mortality rates are 13.8 and 4.67 cases per 100 000 of the female population, respectively, which are lower than in the Eastern Europe (15.7 and 6.3), but higher that in the Northern (8.2 и 2.2) and Western Europe (6.6 и 2.1). The human papillomavirus (HPV) plays a key role in the CC carcinogenesis. The mechanisms of carcinogenesis are related to genetic variations in immunoregulatory factors involved in the induction of proliferation, invasion and metastasis of tumor cells with weakening of the immune control. Among the potential immunogenetic risk factors for the CC development, genetic variants of the TNFα gene rs1800629 and the TLR3 gene rs3775291 have been highlighted, whose associations with CC may be different in various populations and ethnic groups. Aim: To identify the association the -308A TNFα (rs1800629) and 1234C/T TLR3 (rs3775291) genetic polymorphisms with CC development in the patients of the Donbass region of the Russian Federation and to establish the link between these genetic variants and survival. Methods: From February 2021 to December 2024, 320 female patients (the main study group, median age 55 [47; 64] years) with CC stage I to II (TNM) were consecutively recruited to the study. From January 2005 to January 2021, all of them had undergone a radical hysterectomy (Wertheim procedure) in a specialized oncology center, followed by radiation therapy. The control group included 200 healthy women comparable by age (median age 55 [44.75; 63] years, p = 0.101), body mass index (p = 0.513) and smoking status (р = 0.586). In both groups, cervical HPV was diagnosed with polymerase chain reaction (PCR). The genetic variants of TNFα rs1800629 and TLR3 rs3775291 were determined by the SNP-express PCR test systems, TNFα (-308G/A) and TLR3 (Leu412Phe) (Litech, Russia). Results: The incidence of HPV infection in the study group was more than 6.4-fold higher than in the control group (74.1% versus 11.5%, p 0.001). There was an association between СС and the TNFα rs1800629 polymorphism in the co-dominant (χ2 = 8.33; p = 0.016), multiplicative (χ2 = 9.12; p = 0.003), and dominant (χ2 = 7.17; p = 0.008) models; and also with TLR3 rs3775291 polymorphism in the co-dominant (χ2 = 7.47; p = 0.025), multiplicative (χ2 = 6.61; p = 0.011), and dominant (χ2 = 7.17; p = 0.008) models. The patients with the TNFα rs1800629 AA (odds ratio [OR] 2.39, 95% confidence interval [CI)] 0.951–5.994) and GA genotypes (OR 1.46, 95% CI 0.978–2.181), A allele (OR 1.66, 95% CI 1.192–2.311), and the combination of GA + AA genotypes (OR 1.69, 95% CI 1.149–2.481) were at increased risk of СС. In the patients with TLR3 rs3775291 polymorphism, an increased risk of СС was found in the CT (OR 1.42, 95% CI 0.995–2.031) and TT (OR 1.53, 95% CI 0.796–2.932) genotype carriers, in those with the T allele (OR 1.43, 95% CI 1.088–1.878) and the combination of CT + TT (OR 1.63, 95% CI 1.138–2.321). The CC HPV-positive patients with the combination of TNFα rs1800629 GA + AA genotypes, compared to the carriers of the GG genotype, had a decreased overall survival (OS) (p 0.001) and relapse-free survival (RFS) (p = 0.002). The 5-year OS and RFS of the patients with the TNFα rs1800629 GG genotype were 96.13 and 93.55%, and of those with the GA + AA genotypes, 84.15 and 79.27%, respectively. The TLR3 rs3775291 СТ + ТТ carriers, compared to СС, had poorer OS (р = 0.039) and RFS (р = 0.045). The 5-year OS and RFS in the HPV-positive CC patients with the TLR3 rs3775291 СС genotype were 93.94 and 91.92%, and in those with СТ + ТТ genotypes, 90.58 and 86.23%, respectively. Conclusion: The study has shown an association of the genetic variants -308A TNFα (rs1800629) and 1234C/T (rs3775291) with the development of СС and its survival outcomes in the patients of the Donbass region of the Russian Federation. The negative effect of the risk alleles A TNFα rs1800629 and T TLR3 rs3775291 was more common for the CC patients infected with HPV and was associated with worse OS and RFS.