Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer
Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer
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昼夜正反馈环基因的功能多态性预测胃癌术后预后
DOI：
10.1002/cam4.2050
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发表时间：
2019-04-01
期刊：
影响因子：
4
通讯作者：
Qu, Falin
中科院分区：
文献类型：
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作者：
Chen, Yibing;Wang, Dandan;Qu, Falin
背景昼夜节律正反馈环 (CPFL) 基因（CLOCK、BAML1 和 NPAS2）与癌症的发生和进展有关。本研究的目的是探讨CPFL基因中的单核苷酸多态性（SNP）对胃癌（GC）患者预后的影响。方法对704例接受切除的GC患者队列中三个CPFL基因的9个功能性SNP进行基因分型。采用多变量Cox回归模型和Kaplan-Meier曲线进行预后分析。结果9个SNP中，CLOCK中的rs11133399、BAML1中的rs1044432和rs2279284与GC总生存率和无复发生存率显着相关。这些 SNP 的不利基因型显示出对 GC 预后的累积影响。多变量评估模型表明，这些 SNP 与临床变量相结合，增强了预测 GC 预后的能力。此外，生存树分析显示rs11133399基因型是影响GC患者预后的主要危险因素。功能分析表明，rs11133399 中的 G 等位基因比 A 等位基因显着增强荧光素酶报告基因活性。免疫组织化学分析进一步表明，rs11133399的基因型与GC组织中CLOCK的表达水平显着相关，表明该SNP可能通过影响CLOCK基因的表达来影响GC的预后。结论我们的数据表明，CPFL基因中的SNP可能通过影响基因表达来影响GC的临床结果。需要进一步的研究来阐明其潜在的分子机制。
BackgroundCircadian positive feedback loop (CPFL) genes (CLOCK, BAML1, and NPAS2) have been implicated in cancer initiation and progression. The purpose of this study was to explore the effects of single-nucleotide polymorphisms (SNPs) in CPFL genes on prognosis of gastric cancer (GC) patients.MethodsNine functional SNPs from the three CPFL genes were genotyped in a cohort of 704 GC patients undergoing resection. Multivariate Cox regression model and Kaplan-Meier curve were used for prognosis analysis.ResultsAmong the nine SNPs, rs11133399 in CLOCK, rs1044432 and rs2279284 in BAML1 were significantly associated with GC overall survival and recurrence-free survival. The unfavorable genotypes of these SNPs showed a cumulative effect on GC prognosis. Multivariate assessment model indicated that these SNPs, in conjunction with clinical variables, enhanced the power to predict GC prognosis. In addition, survival tree analysis revealed the genotype of rs11133399 as a primary risk factor contributing to the prognosis of GC patients. Functional assays showed that the G allele in rs11133399 significantly enhanced luciferase reporter activity than A allele. Immunohistochemical analysis further demonstrated that the genotype of rs11133399 was significantly associated with the expression level of CLOCK in GC tissues, suggesting that this SNP might affect the prognosis of GC through its influence on the expression of CLOCK gene.ConclusionsOur data indicate that SNPs in CPFL genes might contribute to the clinical outcome of GC through their impact on gene expression. Further studies are needed to elucidate its underlying molecular mechanisms.