Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
Clin Cancer Res. 2011 Nov 15;17(22):7139-47. doi: 10.1158/1078-0432.CCR-11-1134. Epub 2011 Oct 5.
Prognosis of patients with colorectal cancer (CRC) is associated with systemic inflammation, and anti-inflammatory drugs can reduce both CRC incidence and mortality. Genetic variation in proinflammatory pathways can affect an individual's CRC risk. However, few studies have investigated the prognostic importance of this genetic variation in CRC patients.
We investigated the association between CRC survival and genetic variation in proinflammatory pathways among patients from the Puget Sound Surveillance Epidemiology and End Results registry. Single-nucleotide polymorphisms were genotyped in five genes (PTGS-1, PTGS-2, MRP4, NFκB, and IκBKβ). Vital status was ascertained through linkage to the National Death Index. Cox proportional hazards regression was used to calculate HRs and 95% confidence intervals (CI). The false discovery rate method of Benjamini and Hochberg was applied to address multiple testing.
Four PTGS-1 variants were associated with CRC survival. One, G>A intron 9 (rs1213266), was associated with approximately 50% lower CRC mortality (HR(AA/AG vs. GG) = 0.48; 95% CI, 0.25-0.93). Three variants, including L237M, resulted in significantly elevated CRC mortality risk, with HRs ranging from approximately 1.5 to 2.0. Two variants in IκBKβ, including R526Q, were significantly associated with CRC survival. Correction for multiple testing indicated that variants in both PTGS-1 and IκBKβ are reproducibly associated with CRC survival.
Our findings suggest that genetic variation in proinflammatory pathways may be important for CRC prognosis. This investigation represents one of the first descriptions of the relationship between inherited polymorphisms and mortality in CRC patients and provides a starting point for further research.
结直肠癌（CRC）患者的预后与全身炎症有关，而抗炎药物既能降低 CRC 的发病率，也能降低其死亡率。促炎途径中的遗传变异会影响个体的 CRC 风险。然而，很少有研究调查这种遗传变异在 CRC 患者中的预后重要性。
我们研究了来自普吉特湾监测、流行病学和最终结果注册中心的 CRC 患者中促炎途径的遗传变异与 CRC 生存之间的关联。在五个基因（PTGS-1、PTGS-2、MRP4、NFκB 和 IκBKβ）中检测单核苷酸多态性。通过与国家死亡索引的链接确定存活状态。使用 Cox 比例风险回归计算 HR 和 95%置信区间（CI）。应用 Benjamini 和 Hochberg 的错误发现率方法来解决多重检验问题。
四个 PTGS-1 变体与 CRC 生存相关。一个位于内含子 9 的 G>A（rs1213266）与 CRC 死亡率降低约 50%相关（HR（AA/AG 与 GG）=0.48；95%CI，0.25-0.93）。三种变体，包括 L237M，导致 CRC 死亡率显著升高，HR 范围约为 1.5 至 2.0。IκBKβ 中的两个变体，包括 R526Q，与 CRC 生存显著相关。对多重检验的校正表明，PTGS-1 和 IκBKβ 中的变体与 CRC 生存均具有可重复性的关联。
我们的研究结果表明，促炎途径中的遗传变异可能对 CRC 的预后很重要。这项研究代表了对遗传多态性与 CRC 患者死亡率之间关系的首次描述之一，为进一步的研究提供了一个起点。
