Functional Polymorphisms and Gene Expression of TLR9 Gene as Protective Factors for Nasopharyngeal Carcinoma Severity and Progression

Abstract

Nasopharyngeal carcinoma (NPC) is a disease that is closely associated with EBV infection. Toll-like receptor 9 is an important factor mediating the interaction between EBV and the host immune response. Any genetic (single nucleotide polymorphisms, SNPs) or expression variation in TLR9 gene may modify the ability of the receptor to respond correctly to viral infection as in NPC. This study is aimed at evaluating the effect of TLR9 functional polymorphisms (TLR9-1486 T/C and TLR9-1237 T/C) and TLR9 mRNA expression in NPC severity and progression at diagnosis and after treatment. This study included 322 patients with NPC. RFLP-PCR and real-time PCR were used to assess, respectively, the genotypes and the mRNA expression of TLR9 gene. The genotyping analysis showed that the presence of mutated allele -1237C (TLR9-1237 TC+CC) was associated with large tumor size (p = 0.017; OR (CI 95%) = 1.888 (1.11-3.19)) at diagnosis. After treatment, the -1237C allele was associated with a better chance of complete remission (p = 0.031, OR (CI 95%) = 0.486 (0.25-0.95)), a lower risk of distant metastasis (p = 0.028, OR (CI 95%) = 0.435 (0.18-1.02)), and a lower risk of death by NPC (p = 0.003, OR (CI 95%) = 0.20 (0.06-0.67)). Kaplan-Meier analysis showed that patients with -1237CC and -1237TC genotypes had a better overall survival (OVS) (p < 0.01) and distant metastasis-free survival (DMFS) (p < 0.05). A multivariate analysis revealed that TLR9-1237 T/C polymorphism was an independent prognostic factor in OVS (p = 0.02; HR = 0.244) and DMFS (p = 0.048; HR = 0.388). The transcriptomic analysis showed that the mRNA expression was reduced in patients with larger tumor size (T4) (p = 0.013) and advanced clinical stage (SIII-SIV) (p = 0.037). The TLR9 mRNA expression was inversely correlated with tumor size (p = 0.014; r = −0.314) at diagnosis. Our results indicated for the first time that the functional -1237 T/C polymorphism and mRNA expression of TLR9 gene may be considered as protective factors for NPC severity and progression.

Impact of <i>TLR9 </i>and <i>TLR7</i> gene polymorphisms on prognosis and survival of patients with oral squamous cell carcinoma

“…Consistent with our findings, the studied TLR9 rs187084 polymorphism was previously associated with advanced tumor stage and lymph node metastasis in NPC, another subgroup of HNSCC [26]. Another study associated different TLR9 polymorphism rs5743836 (-1237T/C), but not rs187084, with nasopharyngeal carcinoma progression and survival [28].…”

“…Given that immune pathways impact cancer susceptibility, progression, survival, and therapy, there is growing interest in pharmacological targeting of TLRs and the role of their genetic polymorphisms in cancer. However, there are limited data on TLR7 and TLR9 polymorphisms associated with OSCC [25] and HNSCC [26][27][28].…”

“…However, there are limited data on the association between TLR7 and TLR9 polymorphisms and prognosis or susceptibility to oral cancer [24,25] or other subtypes of head and neck squamous cell carcinoma (HNSCC), such as nasopharyngeal carcinoma (NPC) [26][27][28].…”

Predicting AURKA as a novel therapeutic target for NPC: A comprehensive analysis based on bioinformatics and validation

“…Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy originating from the nasopharyngeal epithelium, predominantly in the fossa of Rosenmüller ( Kamran et al, 2015 ; Chua et al, 2016 ; Yosra et al, 2019 ). Globally, newly-diagnosed NPC accounted for 0.7% of all cancer diagnoses in the year 2020, with 133,354 cases ( Sung et al, 2021 ).…”