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.
Highlights
Nasopharyngeal carcinoma (NPC) is a tumor derived from the epithelial cells and usually occurs in the fossa of Rosenmüller
We investigated the association between TLR9 promoter polymorphisms and responses after treatment: recurrence after treatment “No versus Yes,” locoregional recurrence after treatment “No versus Yes,” distant metastasis after treatment “No versus Yes,” and death after treatment and after recurrence “No versus Yes.”
According to the clinicopathological characteristics of NPC at diagnosis, we showed a significantly higher TLR9−1237 TC+CC distribution in the T3-T4 subgroup than in the T1T2 subgroup
Summary
Nasopharyngeal carcinoma (NPC) is a tumor derived from the epithelial cells and usually occurs in the fossa of Rosenmüller. NPC is a distinct entity compared to other epithelial cancers of the head and neck regions in its radiosensitivity, close association with EBV infection, and remarkable geographic distributions. While it is rare in most parts of the world such as Europe and North America, this disease is the major cause of cancer death in China, among people of Cantonese origin where the incidence exceeds 25 per 100000 (man/year). The unequal geographic distribution in NPC incidence suggests that NPC is a multifactorial disease which results from the combined action of multiple etiological factors such as lifestyle, EBV infection, and genetic factors Various environmental factors such as salt-preserved food intake, tobacco consumption, and fume inhalation increase the risk of developing NPC [4, 5]. 13 TLRs have been identified in mammals and 10 in humans [9]
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