Association Between Single Nucleotide Polymorphisms And Risk Of Nasopharyngeal Carcinoma

Part1Functional Genetic Variations in Interleukin-23Receptor andSusceptibility to Nasopharyngeal Carcinoma in Chinese PopulationInterleukin-23receptor (IL-23R) is a key element in the T-helper17(Th17)cell-mediated inflammatory process, which plays an important role in the pathogenesisof cancer. This study examined whether genetic polymorphisms in IL-23R areassociated with nasopharyngeal carcinoma (NPC) susceptibility. A total of1,590cancerpatients and2,136control subjects from eastern and southern Chinese populations weregenotyped. The results revealed that the C allele of the rs10889677A>C polymorphismin the3'UTR of IL-23R gene was inversely associated with nasopharyngeal carcinoma.Healthy control subjects who harbored the rs10889677CC genotype had significantlydecreased cancer risk [odd ratio (OR)=0.57;95%confidence interval (CI)=0.43-0.74]compared to subjects who harbored the rs10889677AA genotype. Biochemical analysisdemonstrated that the rs10889677A allele disrupts the binding site for the microRNAmiR-let-7f, thereby increasing the transcription of the IL-23R gene in vitro and/or invivo. Furthermore, cancer-free individuals expressing the rs10889677CC homozygousgenotype had a lower proportion of regulatory T cells (Tregs) than individualsexpressing the rs10889677AA homozygous genotype in vivo. Upon stimulation withconcanavalin A, cancer-free individuals expressing the rs10889677CC genotype alsohad a higher T-cell proliferation rate than individuals expressing the rs10889677AAgenotype. Subjects carrying the rs10889677AA genotype had higher IL-17and IL-10levels in serum samples than those carrying the rs10889677CC genotype. These resultsindicate that genetic polymorphisms in the IL-23R gene may influence T-cellproliferation, resulting in changes in the levels of Tregs in vivo and modifying cancersusceptibility. Part2Functional NBS1Polymorphism Is Associated With Occurrenceand Advanced Disease Status of Nasopharyngeal CarcinomaAs a component of the MRN (MRE11/RAD50/NBS1) complex, NBS1plays animportant role in cellular response to DNA damage and the maintenance ofchromosomal integrity. The NBS1rs1805794G>C (E185Q) polymorphism has beenfrequently studied in some cancers with discordant results, but its association withnasopharyngeal carcinoma (NPC) in Chinese population has not been investigated.Moreover, there is no report about the association between NBS13'UTR variantrs2735383G>C and the risk of NPC. A multiple center case-control analysis wasperformed to assess the association between NBS1polymorphisms and NPC risk ineastern and southern Chinese population. The genotypes were determined in1052casesand1168controls by using PCR-restriction fragment length polymorphism (PCR-RFLP)assays. Cell migration assays were performed in24-well transwell chambers to detectthe effects of NBS1rs1805794G>C SNP on cell migration. We observed significantdifference in genotype frequencies at the rs1805794G>C site between cases andcontrols (Ptrend<0.0001), the rs1805794CC genotype was associated with substantiallyincreased risk of NPC [odd ratio (OR)=3.87;95%confidence interval (CI)=3.01-5.03],compare with the rs1805794GG genotype. The rs1805794CC genotype increases therisk for invasive disease or metastatic disease, compared with rs1805794GG genotype(OR=2.21;95%CI=1.48-3.26). More over, CNE-2cells (NPC cell line) transfected withpcDNA-NBS1-185Q (rs1805794C) had significantly higher migration levels than thosetransfected with pcDNA-NBS1-185E (rs1805794G, P=0.024). These findings suggestthat E185Q polymorphism in NBS1may be a genetic modifier for the occurrence andaggression of NPC.