Zhang Yi, Wang Peng, Zhou Xing-Chun, Bao Guo-Qiang, Lyu Zhuo-Ming, Liu Xiao-Nan, Wan Shao-Gui, He Xian-Li, Huang Qi-Chao
State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an, China E-mail : huangqichao1@163. com,
Asian Pac J Cancer Prev. 2014;15(11):4637-42. doi: 10.7314/apjcp.2014.15.11.4637.
Hypoxia-inducible factor 1α (HIF-1α) plays an important role in regulating cell survival and angiogenesis, which are critical for tumor growth and metastasis. Genetic variations of HIF1A have been shown to influence the susceptibility to many kinds of human tumors. Increased expression of HIF-1α has also been demonstrated to be involved in tumor progression. However, the prognostic value of single nucleotide polymorphisms (SNPs) in the HIF1A gene remains to be determined in most cancer types, including colorectal cancer (CRC). In this study, we sought to investigate the predictive role of HIF1A SNPs in prognosis of CRC patients and efficacy of chemotherapy.
We genotyped two functional SNPs in HIF1A gene using the Sequenom iPLEX genotyping system and then assessed their associations with clinicopathological parameters and clinical outcomes of 697 CRC patients receiving radical surgery using Cox logistic regression model and Kaplan Meier curves.
Generally, no significant association was found between these 2 SNPs and clinical outcomes of CRC. In stratified analysis of subgroup without adjuvant chemotherapy, patients carrying CT/TT genotypes of rs2057482 exhibited a borderline significant association with better overall survival when compared with those carrying CC genotype [Hazard ratio (HR), 0.47; 95% confidence interval (95% CI): 0.29-0.76; P < 0.01]. Moreover, significant protective effects on CRC outcomes conferred by adjuvant chemotherapy were exclusively observed in patients carrying CC genotype of rs2057482 and in those carrying AC/CC genotype of rs2301113.
Genetic variations in HIF1A gene may modulate the efficacy of adjuvant chemotherapy after surgery in CRC patients.
缺氧诱导因子1α（HIF-1α）在调节细胞存活和血管生成中起重要作用，而细胞存活和血管生成对肿瘤生长和转移至关重要。HIF1A的基因变异已被证明会影响多种人类肿瘤的易感性。HIF-1α表达增加也被证明与肿瘤进展有关。然而，在大多数癌症类型中，包括结直肠癌（CRC），HIF1A基因单核苷酸多态性（SNP）的预后价值仍有待确定。在本研究中，我们试图探讨HIF1A基因SNP对CRC患者预后和化疗疗效的预测作用。
我们使用Sequenom iPLEX基因分型系统对HIF1A基因中的两个功能性SNP进行基因分型，然后使用Cox逻辑回归模型和Kaplan Meier曲线评估它们与697例接受根治性手术的CRC患者的临床病理参数和临床结果之间的关联。
总体而言，这两个SNP与CRC的临床结果之间未发现显著关联。在未接受辅助化疗的亚组分层分析中，与携带CC基因型的患者相比，携带rs2057482的CT/TT基因型的患者总生存率有临界显著关联[风险比（HR），0.47；95%置信区间（95%CI）：0.29-0.76；P<0.01]。此外，仅在携带rs2057482的CC基因型患者和携带rs2301113的AC/CC基因型患者中观察到辅助化疗对CRC结果有显著保护作用。
HIF1A基因的遗传变异可能会调节CRC患者术后辅助化疗的疗效。
