外周血单个核细胞中全球 DNA 低甲基化作为癌症风险的生物标志物。
Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk.
机构信息
Corresponding Author: Simonetta Friso, Department of Medicine, University of Verona School of Medicine, Policlinico G.B. Rossi, P.le L.A. Scuro, 10, 37134 Verona, Italy.
出版信息
Cancer Epidemiol Biomarkers Prev. 2013 Mar;22(3):348-55. doi: 10.1158/1055-9965.EPI-12-0859. Epub 2013 Jan 8.
BACKGROUND
Global DNA hypomethylation is an early molecular event in carcinogenesis. Whether methylation measured in peripheral blood mononuclear cells (PBMCs) DNA is a clinically reliable biomarker for early detection or cancer risk assessment is to be established.
METHODS
From an original sample-set of 753 male and female adults (ages 64.8 ± 7.3 years), PBMCs DNA methylation was measured in 68 subjects with history of cancer at time of enrollment and 62 who developed cancer during follow-up. Age- and sex-matched controls for prevalent and incident cancer cases (n = 68 and 58, respectively) were also selected. Global DNA methylation was assessed by liquid chromatography/mass spectrometry (LC/MS). Methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype and plasma folate concentrations were also determined for the known gene-nutrient interaction affecting DNA methylation.
RESULTS
Cancer subjects had significantly lower PBMCs-DNA methylation than controls [4.39 (95% confidence intervals (CI), 4.25-4.53) vs. 5.13 (95% CI, 5.03-5.21) %mCyt/(mCyt+Cyt); P < 0.0001]. A DNA methylation threshold of 4.74% clearly categorized patients with cancer from controls so that those with DNA methylation less than 4.74% showed an increased prevalence of cancer than those with higher levels (91.5% vs. 19%; P < 0.001). Subjects with cancer at follow-up had, already at enrollment, reduced DNA methylation as compared with controls [4.34 (95% CI, 4.24-4.51) vs. 5.08 (95% CI, 5.05-5.22) %mCyt/(mCyt+Cyt); P < 0.0001]. Moreover, MTHFR677C>T genotype and folate interact for determining DNA methylation, so that MTHFR677TT carriers with low folate had the lowest DNA methylation and concordantly showed a higher prevalence of cancer history (OR, 7.04; 95% CI, 1.52-32.63; P = 0.013).
CONCLUSIONS
Genomic PBMCs-DNA methylation may be a useful epigenetic biomarker for early detection and cancer risk estimation.
IMPACT
This study identifies a threshold for PBMCs-DNA methylation to detect cancer-affected from cancer-free subjects and an at-risk condition for cancer based on genomic DNA methylation and MTHFR677C>T-folate status.
背景
全球 DNA 低甲基化是癌症发生的早期分子事件。外周血单个核细胞（PBMCs）DNA 中测量的甲基化是否是早期检测或癌症风险评估的临床可靠生物标志物，尚待确定。
方法
在 753 名男性和女性成年人（年龄 64.8±7.3 岁）的原始样本集中，对入组时患有癌症的 68 名和随访期间发生癌症的 62 名患者的 PBMCs DNA 甲基化进行了测量。还为现患和新发癌症病例（分别为 68 名和 58 名）选择了年龄和性别匹配的对照。通过液相色谱/质谱（LC/MS）评估全基因组 DNA 甲基化。还确定了亚甲基四氢叶酸还原酶（MTHFR）677C>T 基因型和血浆叶酸浓度，以确定已知影响 DNA 甲基化的基因-营养相互作用。
结果
癌症患者的 PBMCs-DNA 甲基化水平明显低于对照组[4.39（95%置信区间（CI），4.25-4.53）%mCyt/（mCyt+Cyt）与 5.13（95% CI，5.03-5.21）%mCyt/（mCyt+Cyt）；P<0.0001]。4.74%的 DNA 甲基化阈值清楚地将癌症患者与对照组区分开来，因此 DNA 甲基化低于 4.74%的患者比 DNA 甲基化水平较高的患者更易患癌症（91.5%比 19%；P<0.001）。与对照组相比，随访期间患有癌症的患者在入组时已经出现 DNA 甲基化减少[4.34（95% CI，4.24-4.51）%mCyt/（mCyt+Cyt）与 5.08（95% CI，5.05-5.22）%mCyt/（mCyt+Cyt）；P<0.0001]。此外，MTHFR677C>T 基因型和叶酸相互作用决定 DNA 甲基化，因此 MTHFR677TT 携带者叶酸水平较低时 DNA 甲基化最低，并且相应地表现出更高的癌症病史患病率（比值比，7.04；95%置信区间，1.52-32.63；P=0.013）。
结论
基因组 PBMCs-DNA 甲基化可能是早期检测和癌症风险估计的有用表观遗传生物标志物。
影响
本研究确定了 PBMCs-DNA 甲基化的阈值，以检测受癌症影响的患者与无癌症患者，并基于基因组 DNA 甲基化和 MTHFR677C>T-叶酸状态确定癌症风险状况。
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