Ying Gao, Kai Yu, Stephanie Weinstein, Margaret Tucker, Philip Taylor, Demetrius Albanes, Neil Caporaso, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, United States.
World J Gastrointest Oncol. 2012 Aug 15;4(8):193-201. doi: 10.4251/wjgo.v4.i8.193.
To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study.
About 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression.
We found that methylation changes of 31 CpG sites were associated with CRC risk at P < 0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a P value of 1.0 × 10(-4). The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression.
The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.
利用 α-生育酚、β-胡萝卜素癌症预防研究，探讨白细胞 DNA 甲基化与男性吸烟者结直肠癌（CRC）风险的关系。
纳入了 221 例 CRC 病例和 219 例年龄和吸烟强度匹配的对照。使用 Illumina GoldenGate Methylation Cancer Panel I 在研究对象的预诊断血白细胞中评估了从 807 个基因中选择的 1505 个 CpG 位点的 DNA 甲基化。根据每个 CpG 位点在对照中的分布，将甲基化水平分为三分位，用 logistic 回归分析甲基化水平与 CRC 风险的关系。将采血至癌症诊断的时间（根据潜伏期对病例进行分类）纳入进一步使用比例优势回归的分析。
我们发现，31 个 CpG 位点的甲基化变化与 CRC 风险相关，P < 0.01。虽然经过 Bonferroni 校正后，这些位点中没有一个仍然具有统计学意义，但与 CRC 风险最显著相关的 CpG 位点的 P 值达到了 1.0×10(-4)。该 CpG 位点位于 DSP 基因中，CRC 风险的估计值分别为第二和第三三分位与最低三分位相比为 1.52（95%CI：0.91-2.53）和 2.62（95%CI：1.65-4.17）。考虑潜伏期信息后，一些关联得到了加强，这表明相应位点的甲基化水平可能随着肿瘤的进展而随时间发生变化。
结果表明，一些基因的甲基化水平与癌症易感性有关，而另一些基因则与肿瘤随时间的发展有关。需要进一步的研究来证实和完善我们的结果。
