| Background: With the advance of imaging diagnosis and radiation techniques,local control of patients with nasopharyngeal carcinoma(NPC)have significantly improved,distant metastasis remains as the main pattern of treatment failure.How to identify patients with higher risk of distant metastasis became the main obstacle to further improve the prognosis.Clinical stage is critical in predicting prognosis and facilitating treatment planning,however,a significant heterogeneity in treatment outcomes is observed for patients within the same clinical stages,more and more evidences indicated that genetic variations,i.e.single nucleotide polymorphism(SNP),may play an important role in the diversity of treatment outcome.Transforming growth factor-beta(TGF-β)signaling pathway has been reported to be involved in the carcinogenesis and progression of NPC.This study was conducted to evaluated the predicting role of Tag SNPs in TGF-β1/Smad pathway on risk of distant metastasis in 496 NPC patients in Chinese Han Population.Methods: This study included 496 patients with histologically diagnosed non-metastatic NPC who were recruited between January 2012 and May 2013 at Fujian Provincial Cancer Hospital and had blood samples available for analysis,all of them were treated with intensitymodulated radiation therapy(IMRT).Twelve Tag SNPs from core genes of TGF-β1/Smad pathway were genotyped by matrix-assisted laser desorption/ionization-time of flight mass spectro-photometry with the Mass ARRAY platform and Taq Man assay.We then evaluated potential associations of Tag SNPs with the subsequent development of distant failure,the cumulative incidence of which was estimated with Kaplan-Meier analysis.Multivariate Cox regression analysis was used to analyze correlations between genetic variants and the occurrence of distant metastasis.In addition,the plasma TGF-β1 was detected in 147 patients by Enzyme-Linked Immunosorbnent Assay(ELISA),in order to evaluated the impact of different TGF-β1 genotypes on TGF-β1 level in plasma.Results: The median follow-up time was 40 months(range 4~51 months)for the whole cohort,with the 3-year overall survival(OS)and distant metastasis free survival(DMFS)shown to be 91.8% and 85.1%,respectively.After genotyping,only TGF-β1: rs1800469 and TGF-β1: rs1800470 were found to be independent prognostic factors for distant failure.Patients who carried TGF-β1: rs1800469 CC genotype had significant higher risk of distant metastasis(HR 0.560,95%CI 0.335-0.936,P=0.027),especially for those with advanced disease.Patients with TGF-β1: rs1800470 TT genotype also presented with significant higher risk of distant failure(HR 0.499,95%CI 0.301-0.827,P=0.007),the same effect remained significant in subgroup analysis(early stage vs.advanced stage).We further found that these two SNPs had a cumulative effect on metastasis risk,with that risk being highest for patients carrying both of these unfavorable genotypes,and those carried no unfavorable genotypes had the lowest risk of distant failure(P=0.012).No significant association was found between plasma TGF-β1 and genotypes of these two significant SNPs(P>0.05).Conclusions: Two Tag SNPs,TGF-β1: rs1800469 and TGF-β1: rs1800470,within TGF-β1/Smad signaling pathway were found to be significantly associated with the risk of distant metastasis in NPC paitents.These two Tag SNPs were indicated to have a cumulative effect on distant metastasis risk.Their effect on the risk of metastasis may not be through regulation of plasma levels of TGF-β1,further research is needed to unravel the functional significance of these polymorphisms.If our results could be replicate in other centers and races through independent population,it may be benefit for selecting patient subgroups at high risk of distant metastasis,thereby helping to refine therapeutic decisions in the treatment of NPC.Background: Distant metastasis is the main pattern of treatment failure in nasopharyngeal carcinoma(NPC)patients.How to identify patients with higher risk of distant metastasis became the main obstacle to further improve the prognosis.Clinical stage is critical in predicting prognosis and facilitating treatment planning,however,a significant heterogeneity in treatment outcomes is observed for patients within the same clinical stages,more and more evidences indicated that genetic variations,i.e.single nucleotide polymorphism(SNP),may play an important role in the diversity of treatment outcome.Transforming growth factorbeta(TGF-β)signaling pathway has been reported to be involved in the carcinogenesis and progression of NPC.In part I,we found that genetic variation in TGF-β 1/Smad were significantly associated with risk of distant metastasis,in this part,we aimed to evaluated the predicting role of Tag SNPs in Smad-independent pathway,i.e.PI3K/PTEN/AKT/m TOR,on risk of distant failure in 496 NPC patients in Chinese Han Population.Methods: This study included 496 patients with histologically diagnosed non-metastatic NPC who were recruited between January 2012 and May 2013 at Fujian Provincial Cancer Hospital and had blood samples available for analysis,all of them were treated with intensitymodulated radiation therapy(IMRT).Sixteen Tag SNPs from core genes of PI3K/PTEN/AKT /m TOR pathway were genotyped by matrix-assisted laser desorption/ ionization-time of flight mass spectro-photometry with the Mass ARRAY platform and Taq Man assay.We then evaluated potential associations of Tag SNPs with the subsequent development of distant failure,the cumulative incidence of which was estimated with Kaplan-Meier analysis.Multivariate Cox regression analysis was used to analyze correlations between genetic variants and the occurrence of distant metastasis.In addition,recursive partitioning analysis(RPA)was introduced to integrate the favorable genotype and anatomic factor to establish the RPA model,Akaike information criterion(AIC)and Harrell’s concordance index(C-index)were applied to compare the prognostic ability of RPA model,N category and clinical stage.Results: The median follow-up time was 40 months(range 4-51 months)for the whole cohort,with the 3-year overall survival(OS)and distant metastasis free survival(DMFS)shown to be 91.8% and 85.1%,respectively.After genotyping,only AKT1: rs3803300 和 AKT1: rs2494738 were identified as independent predicting factors for distant metastasis.Patients with AKT1: rs3803300 GG and AKT1:rs2494738 GA/AA genotype had significant higher risk of distant failure(AKT1: rs3803300 HR 0.536,95%CI 0.292-0.986,P=0.045;AKT1: rs2494738 HR 0.530,95%CI 0.302-0.929,P=0.027).Patients with unfavorable genotype also showed to had inferior DMFS than those without unfavorable genotype(HR 0.443,95% CI 0.264-0.744,P =0.002).We found that genetic variation may had some joint effect with N classification in recursive-partitioning analysis(RPA)analysis,with which patients were stratified into four different risk subgroups: RPA1(low risk,N0-1 without unfavorable genotype),RPA2(moderate risk,N0-1 with unfavorable genotype),RPA3(high risk,N2-3 without unfavorable genotype)and RPA4(highest risk,N2-3 with unfavorable genotype).This RPA model showed significant prognostic value for distant metastasis(HR 1.846,95% CI 1.443-2.361,P <0.001),which was better than N category or clinical stage,with the lowest AIC value and highest c-index.Conclusions: Two Tag SNPs,AKT1: rs3803300 and AKT1:rs2494738,within PI3K/PTEN/ AKT/m TOR signaling pathway were found to be significantly associated with the risk of distant metastasis in NPC paitents.The RPA model,which was established by these two Tag SNPs and N category,presented as the best predicting model for risk of distant failure,when compared with N category and clinical stage.Further research is needed to unravel the functional significance of these polymorphisms.If our results could be replicate in other centers and races through independent population,it may be benefit for selecting patient subgroups at high risk of distant metastasis,thereby helping to refine therapeutic decisions in the treatment of NPC. |
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