Polymorphisms in toll-like receptor 3 and 4 genes as prognostic and outcome biomarkers in melanoma patients

Abstract

Melanoma is one of the most aggressive tumors, and in the setting of rising incidence and mortality, there is an urgent need to identify new prognostic markers. Toll-like receptors (TLRs), are aberrantly expressed in numerous cancers, including melanoma. TLR signaling provides a microenvironment that is involved in antitumor immune response, chronic inflammation, cancer cell proliferation and evasion of immune destruction. In the present study, we investigated whether single nucleotide polymorphisms (SNPs) in TLR3 and TLR4 genes are associated with clinicopathologic features, progression and survival of melanoma patients. The study was conducted on 120 melanoma patients. DNA extracted from peripheral blood was genotyped for TLR3 polymorphisms rs5743312 and rs3775291 (L412F) and TLR4 polymorphisms rs4986790 (D299G) and rs4986791 (T399I), by TaqMan Real-Time PCR Assays. Kaplan–Meier survival curves were compared by the log-rank test. TLR3 polymorphism L412F was associated with a higher mitotic index (P = 0.035). TLR4 D299G and T399I polymorphisms were associated with indicators of melanoma severity, nodal metastases (P = 0.005 and P = 0.007, respectively) and advanced stage III (P = 0.005 and P = 0.004, respectively). Cox regression analysis showed that the presence of tumor-infiltrating lymphocytes (TILs) predicted better overall survival (HR = 0.318; P = 0.004). TLR4 T399I polymorphism was significantly associated with worse survival, P = 0.025. The overall survival rates were significantly lower for patients carrying variant allele T of TLR4 T399I SNP (TC and TT genotypes combined) (P = 0.008, log-rank test), compared to wild-type genotype CC. Our findings indicate that TLR4 polymorphisms T399I (rs4986791) and D299G (rs4986790) could be potential prognostic and survival markers for melanoma patients.

Genetic Association of Toll-Like Receptor 4 (TLR4) Gene Polymorphism (rs4986790) With Oral Squamous Cell Carcinoma (OSCC): A Pilot Case-Control Study

“…The study population included 120 patients, and the genotyping was carried out employing TaqMan real-time PCR assay. The TLR4 D299G and T399I variants were associated with nodal metastasis, advanced stage III, and severity of melanoma [ 27 ]. A very recent study by Jha and colleagues demonstrated that the AG genotype and the G allele were found to be the risk genotype and risk allele in the population studied.…”

Impact of Pattern Recognition Receptors on the Prognosis of Chemotherapy-treated Rectal Cancer Patients

“…Recently, increasing evidence has suggested that these DAMPs can serve as powerful immunological adjuvants, eliciting antitumor immunity and increasing anticancer therapy efficacy (11,12,15,23). However, SNPs in PRRs can alter receptor function to affect the immune response and therapeutic response (17,20,21,(26)(27)(28)(29). For example, RAGE G82S is associated with chemotherapy response and clinical outcomes in non-small cell lung cancer, while P2RX7 E496A is related to overall survival outcome in chronic lymphocytic leukemia patients (28,29).…”

TLR and Cancer: The Enigmatic Cross Talk

“…Whereas TLR4 D299G and T399I polymorphisms were associated with melanoma severity, nodal metastases, and advanced stage III and could be then potential markers targeting the survival and prognostic of melanoma patients. TLR4 T399I polymorphism was highly correlated with worse survival [130]. However, no association between TLR7 single nucleotide G pp.…”