| Introduction: Distant metastasis was primary failure pattern for newly diagnosed non-metastatic nasopharyngeal carcinoma(NPC) after chemoradiotherapy. How to evaluate and predict metastatic risk for nasopharyngeal carcinoma became an advanced research hotspot. A lot of studies showed that host genetics were significant factors of developing distant metastasis. This study aimed to investigate the association between single nucleotide polymorphisms(SNP) of the TGF-?(transforming growth factor-beta) signaling pathway and prognosis of nasopharyngeal carcinoma.Methods and materials: Two hundred ninety-two patients with nasopharyngeal carcinoma without distant metastasis, which diagnosed by pathology in Fujian Provincial Cancer Hospital, between October 2005 and December 2010. DNA was extracted from peripheral blood samples that come from patients before treatment. This study genotyped 12 SNP from 5 genes in the TGF-? signaling pathway using matrix-assisted laser desorption/ionization-time of flight mass spectrophotometry(Mass ARRAY) or Taq Man method. Using Kaplan-Meier method calculate survival rate, then univariate analysis assess the prognosis of nasopharyngeal carcinoma using log-rank test, and multivariate analysis study the association of gene polymorphism and prognosis by Cox proportional hazards model.Results: The median follow-up time was 39.5 months(5-49 months), 44 people developed distant metastasis and 29 patient died in follow-up. The 3-year estimate distant metastasis-free survival(DMFS) rate and Overall survival(OS) rate respectively were 85.0% and 91.2%. Univariate analysis indicated that TGF-?1 gene:rs1800469 CC genotype has a lower DMFS rate compared with CT/TT genotype(74.1%vs.87.9%, p=0.011); and rs1800470 TT genotype also has a lower DMFS rate compared with CT/CC(72.2%vs.87.8%, p=0.004); and Smad4 gene: rs12598604 AA genotype has a higher DMFS rate than AG/GG genotype;while other SNPs had no differences in DMFS. Univariate analysis also indicated that rs1800469CT/TT genotype has a higher OS rate than CC genotype(93.7% vs. 82.3%, p=0.010). Cox multivariate analysis showed that rs1800469 CT/TT genotype is associated with a significantly lower distant metastatic risk than the CC genotype(HR=0.539,p=0.045); rs1800470 TT genotype was associated with high distant metastatic risk than CT/CC genotype(HR=2.304,p=0.007); and rs12598604 AG/GG genotype is associated with poor DMFS than AA genotype(HR=2.362,p=0.038); rs1800469 CT/ TT genotype is associated with lower mortality risk than CC genotype(HR=0.462, p=0.042). In addition, analyzing combined subgroups, these rates showed higher for those having both the CC genotype of rs1800469 and the TT genotype of rs1800470(HR=2.288, 95%CI: 1.244-4.209, p=0.008). The three-year metastasis-free survival rate of patients with three unfavorable genotypes, and one or two unfavorable genotypes, and non-unfavorable genotype are 60.0%, 85.0%, and 93.5% respectively. The difference was statistically significant(p<0.001). Multivariate analysis showed that patients with one or two unfavorable genotypes distant metastasis risk ratio of 2.471(p=0.090), while carrying three unfavorable genotypes hazard ratio of 5.949(p=0.003), compared with non-unfavorable genotypes.Conclusions: The study found that 3 SNP sites of gene in TGF-?/Smad signal pathway were associated with different risk of distant metastasis, and rs1800469 CC genotype, rs1800470 TT genotype and rs12598604 AG/GG genotype are associated with risk of distant metastasis in patients with NPC. The three single nucleotide sites could become stable and effective genetic marker for predicting distant metastasis risk. This study also show that rs1800469 CC genotype is unfavorable prognostic factor for overall survival. These three SNP sites may become indicators of distant metastasis risk and effective genetic markers, but still need to be confirmed by larger samples and functional experiments. |
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