Pathology and Laboratory Medicine, Brown University, Providence, RI 02912, USA.
J Clin Oncol. 2011 Mar 20;29(9):1133-9. doi: 10.1200/JCO.2010.31.3577. Epub 2011 Feb 22.
Epigenetic alterations in tissues targeted for cancer play a causal role in carcinogenesis. Changes in DNA methylation in nontarget tissues, specifically peripheral blood, can also affect risk of malignant disease. We sought to identify specific profiles of DNA methylation in peripheral blood that are associated with bladder cancer risk and therefore serve as an epigenetic marker of disease susceptibility.
We performed genome-wide DNA methylation profiling on participants involved in a population-based incident case-control study of bladder cancer.
In a training set of 112 cases and 118 controls, we identified a panel of 9 CpG loci whose profile of DNA methylation was significantly associated with bladder cancer in a masked, independent testing series of 111 cases and 119 controls (P < .0001). Membership in three of the most methylated classes was associated with a 5.2-fold increased risk of bladder cancer (95% CI, 2.8 to 9.7), and a model that included the methylation classification, participant age, sex, smoking status, and family history of bladder cancer was a significant predictor of bladder cancer (area under the curve, 0.76; 95% CI, 0.70 to 0.82). CpG loci associated with bladder cancer and aging had neighboring sequences enriched for transcription-factor binding sites related to immune modulation and forkhead family members.
These results indicate that profiles of epigenetic states in blood are associated with risk of bladder cancer and signal the potential utility of epigenetic profiles in peripheral blood as novel markers of susceptibility to this and other malignancies.
癌症靶组织中的表观遗传改变在癌变中起因果作用。非靶组织（特别是外周血）中 DNA 甲基化的变化也可能影响恶性疾病的风险。我们试图确定与膀胱癌风险相关的外周血中特定的 DNA 甲基化谱，作为疾病易感性的表观遗传标志物。
我们对参与膀胱癌基于人群的病例对照研究的参与者进行了全基因组 DNA 甲基化分析。
在 112 例病例和 118 例对照的训练集中，我们确定了一组 9 个 CpG 位点，其 DNA 甲基化谱在一个经过掩蔽的独立测试系列（111 例病例和 119 例对照）中与膀胱癌显著相关（P<.0001）。在三个甲基化程度最高的类别中，有成员的膀胱癌风险增加了 5.2 倍（95%CI，2.8 至 9.7），包括甲基化分类、参与者年龄、性别、吸烟状况和膀胱癌家族史的模型是膀胱癌的显著预测因素（曲线下面积为 0.76；95%CI，0.70 至 0.82）。与膀胱癌和衰老相关的 CpG 位点具有转录因子结合位点相关的邻近序列，这些序列与免疫调节和叉头家族成员有关。
这些结果表明，血液中表观遗传状态的特征与膀胱癌风险相关，并表明外周血中表观遗传谱作为这种和其他恶性肿瘤易感性的新型标志物的潜在应用。
