TGF-β信号通路基因单核苷酸多态性与鼻咽癌预后的关联性研究

发布时间：2019-05-18 05:27

【摘要】：目的:远处转移是初诊无转移性鼻咽癌放化疗后最主要的失败原因,预测鼻咽癌病人远处转移风险是临床研究重点和热点。不少研究发现宿主本身的遗传特质是转移发生发展的重要影响因素。该研究旨在探讨转化生长因子β(transforming growth factor-beta,TGF-β)信号通路中基因的单核苷酸多态性(Single Nucleotide Polymorphism,SNP)与鼻咽癌预后的关联性。材料和方法:入组2012.01-2012.12于我院就诊且经病理确诊的初诊无远处转移并且接受调强放射治疗的患者。从外周血液标本中提取每个患者的基因组DNA,所有血液标本的收集均在患者接受治疗前。本研究共入组鼻咽癌病例292例。本研究选择TGF-β信号通路的5个基因12单核苷多态性位点,采用基质辅助激光解吸附电离飞行时间质谱或Taq Man方法进行SNP检测分型。采用Kaplan Meier(KM)法计算生存率,单因素分析采用log-rank检验,并采用Cox比例风险模型进行多因素分析,探讨基因多态性与鼻咽癌预后的关联。结果:全组中位随访时间为39.5月(5-49月),44例出现了远处转移,29例死亡。全组病人的3年无远处转移生存率为85.0%,3年总生存率为91.2%。单因素分析发现:TGF-β1基因rs1800469位点CC基因型比CT/TT型的无远处转移生存率低(74.1%vs.87.9%,p=0.011);TGF-β1基因rs1800470位点的TT基因型与CT/CC型相比,TT型的无远处转移生存率更低(72.2%vs.87.8%,p=0.004);Smad4基因rs12958604位点AA型的无远处转移生存率高于AG/GG型(90.0%vs.80.6%,p=0.028),其余各SNP位点不同基因型患者的无转移生存差异均未达到统计学差异(p0.05)。单因素也显示rs1800469CT/TT基因型为总生存率高于CC型(93.7%vs.82.3%,p=0.010)。Cox多因素分析发现:rs1800469位点CT/TT型的转移风险比CC型低(HR=0.539,p=0.045),rs1800470位点TT型的转移风险比CT/CC型高(HR=2.304,p=0.007),rs12958604位点AG/GG的转移风险比AA型高(HR=2.362,p=0.038);rs1800469的CT/TT基因型为死亡风险低于CC型(HR=0.462,p=0.042)。此外,将无转移生存存在统计学差异的3个位点结合分析发现,同时携带3个高转移风险基因型的3年无转移生存率为60.%,携带1个或2个为85.0%,无携带者为93.5%,差异具有统计学意义(p0.001)。多因素分析显示与不携带不利基因型相比携带1个或2个不利基因型的远处转移风险比为2.471(p=0.090),同时携带3个不利基因型的风险比为5.949(p=0.003)。结论:本研究发现TGF-β信号通路中存在三个单核苷酸多态性位点与鼻咽癌的远处转移风险相关,rs1800469 CC基因型、rs1800470 TT基因型和rs12598604AG/GG存在较高的远处转移风险。联合分析显示能更好评估和预测鼻咽癌转移风险。研究也发现rs1800469 CC基因型是鼻咽癌总生存预后差的一个因素。这三个单核苷酸位点可能成为预测鼻咽癌远处转移风险的稳定有效的遗传标记物,有待于扩大样本量进一步证实及进一步的功能实验验证。
[Abstract]:Objective: distant metastasis is the most important cause of failure after radiotherapy and chemotherapy for newly diagnosed non-metastasis nasopharyngeal carcinoma (NPC). Predicting the risk of distant metastasis in patients with nasopharyngeal carcinoma (NPC) is the focus and focus of clinical research. Many studies have found that the genetic characteristics of the host itself are an important factor affecting the occurrence and development of metastasis. The purpose of this study was to investigate the relationship between single nucleotide polymorphism (Single Nucleotide Polymorphism,SNP) of transforming growth factor 尾 (transforming growth factor-beta,TGF- 尾) signaling pathway and prognosis of nasopharyngeal carcinoma (NPC). Materials and methods: the patients who were admitted to our hospital in 2012.01 / 2012.12 and diagnosed pathologically did not have distant metastasis and received intensity modulation radiotherapy. Genomic DNA, was extracted from peripheral blood samples. All blood samples were collected before treatment. 292 cases of nasopharyngeal carcinoma (NPC) were enrolled in this study. In this study, five mononucleosides polymorphism sites of TGF- 尾 signaling pathway were selected, and SNP typing was detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry or Taq Man. The survival rate was calculated by Kaplan 鈮，

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