Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Cancer Epidemiol Biomarkers Prev. 2012 Aug;21(8):1293-302. doi: 10.1158/1055-9965.EPI-12-0361. Epub 2012 Jun 19.
Blood leukocytes from patients with solid tumors exhibit complex and distinct cancer-associated patterns of DNA methylation. However, the biologic mechanisms underlying these patterns remain poorly understood. Because epigenetic biomarkers offer significant clinical potential for cancer detection, we sought to address a mechanistic gap in recently published works, hypothesizing that blood-based epigenetic variation may be due to shifts in leukocyte populations.
We identified differentially methylated regions (DMR) among leukocyte subtypes using epigenome-wide DNA methylation profiling of purified peripheral blood leukocyte subtypes from healthy donors. These leukocyte-tagging DMRs were then evaluated using epigenome-wide blood methylation data from three independent case-control studies of different cancers.
A substantial proportion of the top 50 leukocyte DMRs were significantly differentially methylated among head and neck squamous cell carcinoma (HNSCC) cases and ovarian cancer cases compared with cancer-free controls (48 and 47 of 50, respectively). Methylation classes derived from leukocyte DMRs were significantly associated cancer case status (P < 0.001, P < 0.03, and P < 0.001) for all three cancer types: HNSCC, bladder cancer, and ovarian cancer, respectively and predicted cancer status with a high degree of accuracy (area under the curve [AUC] = 0.82, 0.83, and 0.67).
These results suggest that shifts in leukocyte subpopulations may account for a considerable proportion of variability in peripheral blood DNA methylation patterns of solid tumors.
This illustrates the potential use of DNA methylation profiles for identifying shifts in leukocyte populations representative of disease, and that such profiles may represent powerful new diagnostic tools, applicable to a range of solid tumors.
实体瘤患者的血液白细胞表现出复杂而独特的与癌症相关的 DNA 甲基化模式。然而，这些模式背后的生物学机制仍知之甚少。由于表观遗传生物标志物为癌症检测提供了重要的临床潜力，我们试图解决最近发表的研究工作中的一个机制空白，假设基于血液的表观遗传变异可能是由于白细胞群体的变化所致。
我们使用健康供者外周血白细胞亚群的全基因组 DNA 甲基化谱，鉴定白细胞亚群中的差异甲基化区域（DMR）。然后，我们使用来自三个不同癌症病例对照研究的全基因组血液甲基化数据来评估这些白细胞标记 DMR。
在头颈部鳞状细胞癌（HNSCC）病例和卵巢癌病例与无癌症对照相比，前 50 个白细胞 DMR 中有相当大一部分显著甲基化差异（分别为 48 个和 47 个）。从白细胞 DMR 衍生的甲基化类别与所有三种癌症类型的癌症病例状态显著相关（P < 0.001，P < 0.03 和 P < 0.001）：HNSCC、膀胱癌和卵巢癌，分别并以高精度预测癌症状态（曲线下面积 [AUC] = 0.82、0.83 和 0.67）。
这些结果表明，白细胞亚群的变化可能占实体瘤外周血 DNA 甲基化模式变异性的相当大一部分。
这说明了 DNA 甲基化谱用于识别代表疾病的白细胞群体变化的潜力，并且这些谱可能代表强大的新诊断工具，适用于多种实体瘤。
