Department of General Surgery, Tangdu Hospital, Xi'an, China.
Cancer. 2012 Feb 15;118(4):937-46. doi: 10.1002/cncr.26348. Epub 2011 Jul 19.
Previous studies have demonstrated that circadian genes play a role in the development and progression of many cancers. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in circadian genes on recurrence and survival of colorectal cancer (CRC) patients.
Nine functional SNPs in 3 genes (CLOCK, NPAS2, and BMAL1) on the circadian positive feedback loop were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 411 resected Chinese CRC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis.
The authors identified 2 SNPs in the CLOCK gene to be significantly associated with CRC overall survival. SNP rs3749474 exhibited a significant association with survival of CRC patients in the additive model (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.37-0.81; P = .003). In addition, patients carrying the heterozygous variant of rs1801260 had significantly increased overall survival compared with those carrying homozygous wild-type genotype (HR, 0.31; 95% CI, 0.11-0.88; P = .03). Findings from functional assay provided further biological support for these significant associations. Stratified analysis found no modifying effect of chemotherapy on the prognostic significance of both SNPs. Moreover, we observed cumulative effects of these 2 SNPs on CRC overall survival (P for trend = .01). Compared with patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 2.92-fold increased risk of death (P = .03).
The results suggest for the first time that CLOCK gene polymorphisms may serve as an independent prognostic marker for CRC patients.
先前的研究表明，生物钟基因在许多癌症的发生和发展中发挥作用。本研究旨在评估生物钟基因中的单核苷酸多态性（SNP）对结直肠癌（CRC）患者复发和生存的影响。
选择生物钟正反馈环上的 3 个基因（CLOCK、NPAS2 和 BMAL1）中的 9 个功能 SNP，使用 Sequenom iPLEX 基因分型系统对 411 例切除的中国 CRC 患者进行基因分型。多变量 Cox 比例风险模型和 Kaplan-Meier 曲线用于预后分析。
作者确定了 CLOCK 基因中的 2 个 SNP 与 CRC 总生存显著相关。SNP rs3749474 在加性模型中与 CRC 患者的生存显著相关（风险比[HR]，0.55；95%置信区间[CI]，0.37-0.81；P =.003）。此外，与携带纯合野生型基因型的患者相比，携带杂合变异型 rs1801260 的患者总生存明显增加（HR，0.31；95%CI，0.11-0.88；P =.03）。功能测定的结果为这些显著相关性提供了进一步的生物学支持。分层分析发现，化疗对这两个 SNP 的预后意义没有修饰作用。此外，我们观察到这两个 SNP 对 CRC 总生存的累积效应（P 趋势 =.01）。与无不利基因型的患者相比，携带 2 个不利基因型的患者死亡风险增加 2.92 倍（P =.03）。
这些结果首次表明，CLOCK 基因多态性可能是 CRC 患者的独立预后标志物。
