Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients.
Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients.
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昼夜节律负反馈调节基因的遗传多态性预测胃癌患者的总体生存率和化疗反应
DOI：
10.1038/srep22424
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发表时间：
2016-03-01
影响因子：
4.6
通讯作者：
Bao G
中科院分区：
文献类型：
--
作者：
Qu F;Qiao Q;Wang N;Ji G;Zhao H;He L;Wang H;Bao G
昼夜节律负反馈环(CNFL)基因在肿瘤的发生发展中起重要作用。为探讨CNFL基因单核苷酸多态(SNPs)对胃癌患者生存的影响，对1030例胃癌切除患者(训练组704例，验证组326例)进行了5个CNFL基因的13个功能性SNPs基因分型，以探讨SNPs与总生存期(OS)的关系。在13个SNP中，有3个SNP(CRY1中的rs1056560、PER1中的rs3027178和PER3中的rs228729)与训练集中的GC的OS显著相关，并在验证集和合并分析中得到验证。此外，观察到这些SNPs对GC存活率具有剂量依赖的累积效应，生存树分析显示这些SNPs之间存在较高的顺序交互作用。此外，在rs1056560变异等位基因(TG/GG)的患者中观察到辅助化疗(ACT)对GC的保护作用，而在纯合子野生型(TT)患者中未观察到ACT对GC的保护作用。功能分析表明rs1056560基因对癌细胞CRY1的表达有显著影响。我们的研究表明，CNFL基因中的SNPs可能与GC的预后有关，并为选择对ACT最有可能敏感的GC患者提供了指导。
Circadian negative feedback loop (CNFL) genes play important roles in cancer development and progression. To evaluate the effects of single nucleotide polymorphisms (SNPs) in CNFL genes on the survival of GC patients, 13 functional SNPs from 5 CNFL genes were genotyped in a cohort of 1030 resected GC patients (704 in the training set, 326 in the validation set) to explore the association of SNPs with overall survival (OS). Among the 13 SNPs, three SNPs (rs1056560 in CRY1, rs3027178 in PER1 and rs228729 in PER3) were significantly associated with OS of GC in the training set, and verified in the validation set and pooled analysis. Furthermore, a dose-dependent cumulative effect of these SNPs on GC survival was observed, and survival tree analysis showed higher order interactions between these SNPs. In addition, protective effect conferred by adjuvant chemotherapy (ACT) on GC was observed in patients with variant alleles (TG/GG) of rs1056560, but not in those with homozygous wild (TT) genotype. Functional assay suggested rs1056560 genotypes significantly affect CRY1 expression in cancer cells. Our study presents that SNPs in the CNFL genes may be associated with GC prognosis, and provides the guidance in selecting potential GC patients most likely responsive to ACT.