Li Qiuchen, Qu Falin, Li Renli, He Xianli, Zhai Yulong, Chen Weigang, Zheng Yong
Department of Gastroenterology, First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, 832008, China.
Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710038, China.
Oncotarget. 2017 Dec 2;8(67):110861-110876. doi: 10.18632/oncotarget.22864. eCollection 2017 Dec 19.
Growing evidence has indicated that single-stranded DNA-binding proteins 1 () is involved in tumor initiation and progression. However, effects of single nucleotide polymorphisms (SNPs) in gene on gastric cancer (GC) prognosis are still unknown. In present study, two functional SNPs from were selected and genotyped in a large cohorts of 1030 resected GC patients (326 in the training set, 704 in the validation set) to explore the association of SNPs with patients' survival. The rs6976500 G allele (CG/GG) genotypes were found significantly associated with both worse overall survival (OS) and recurrence-free survival (RFS) in the training and the independent validation set when compared to C allele genotype, which reaching a more robust statistical significance in the pooled analysis. Furthermore, integration of rs6976500 genotypes and TNM stage significantly improved the prognosis prediction models based on TNM stage alone. In addition, only carriers with at least one G allele of rs6976500 gained significant survival benefit from FOLFOX-based ACT. Mechanistically, SNP rs6976500 G allele genotype could significantly decrease promoter transcriptional activity and markedly reduce expression level of compared with the C allele genotype in GC cells. This was further substantiated by immunohistochemical assay in 70 GC tissue samples. Our study presents the first evidence that SNP rs6976500 G allele genotypes might contribute to GC prognosis by attenuating promoter activity and gene expression, and provides the guidance in refining therapeutic decisions of GC patients. Further exploration on its function is needed to clarify the exact biological mechanism behind.
越来越多的证据表明，单链DNA结合蛋白1（）参与肿瘤的发生和发展。然而，基因中的单核苷酸多态性（SNP）对胃癌（GC）预后的影响仍不清楚。在本研究中，从基因中选择了两个功能性SNP，并在1030例接受手术切除的GC患者的大型队列中进行基因分型（训练集326例，验证集704例），以探讨SNP与患者生存的相关性。与C等位基因基因型相比，发现rs6976500 G等位基因（CG/GG）基因型在训练集和独立验证集中均与较差的总生存期（OS）和无复发生存期（RFS）显著相关，在汇总分析中达到更强的统计学显著性。此外，将rs6976500基因型与TNM分期相结合显著改善了仅基于TNM分期的预后预测模型。此外，只有rs6976500至少有一个G等位基因的携带者从基于FOLFOX的辅助化疗中获得显著的生存益处。机制上，与GC细胞中的C等位基因基因型相比，SNP rs6976500 G等位基因基因型可显著降低启动子转录活性，并显著降低的表达水平。在70例GC组织样本中的免疫组织化学分析进一步证实了这一点。我们的研究首次证明，SNP rs6976500 G等位基因基因型可能通过减弱启动子活性和基因表达而影响GC预后，并为优化GC患者的治疗决策提供指导。需要进一步探索其功能以阐明背后的确切生物学机制。
