Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk.
Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk.
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DOI：
10.1158/1055-9965.epi-12-0859
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
Choi SW
中科院分区：
文献类型：
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作者：
Friso S;Udali S;Guarini P;Pellegrini C;Pattini P;Moruzzi S;Girelli D;Pizzolo F;Martinelli N;Corrocher R;Olivieri O;Choi SW
整体DNA低甲基化是癌发生的早期分子事件。在外周血单核细胞（PBMC）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。从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68名在入组时有癌症病史的受试者和62名在随访期间发生癌症的受试者进行了PBMC DNA甲基化检测。还选择了流行和偶发癌症病例的年龄和性别匹配对照（分别为n=68和n=58）。通过LC/MS评估总体DNA甲基化。还确定了亚甲基四氢叶酸还原酶（MTHFR）677 C>T基因型和血浆叶酸浓度，以用于已知的影响DNA甲基化的基因-营养相互作用。癌症受试者PBMCs-DNA甲基化显著低于对照组[4.39（95%CI 4.25-4.53）vs. 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<4.74%的患者比DNA甲基化水平较高的患者显示出癌症患病率增加（91.5% vs. 19%;P <0.001）。与对照组相比，随访时的癌症受试者在入组时已经降低了DNA甲基化[4.34（95%CI 4.24-4.51）vs. 5.08（95%CI 5.05-5.22）%mCyt/（mCyt+Cyt），P<0.0001]。此外，MTHFR 677 C>T基因型和叶酸相互作用以确定DNA甲基化，MTHFR 677 TT基因携带者中，叶酸水平低者DNA甲基化水平最低，癌症史患病率高（OR= 7.04，95%CI1.52 -32.63，P=0.013）。基因组PBMCs-DNA甲基化可能是一个有用的表观遗传生物标志物，用于早期检测和癌症风险评估。该研究确定了PBMC-DNA甲基化的阈值，以检测来自无癌症受试者的癌症影响，并基于基因组DNA甲基化和MTHFR 677 C> T-叶酸状态检测癌症的风险状况。
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. From an original sample-set of 753 male and female adults(aged 64.8±7.3years),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 n=58,respectively)were also selected. Global DNA methylation was assessed by LC/MS. Methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype and plasma folate concentrations were also determined for the known gene-nutrient interaction affecting DNA methylation. Cancer subjects had significantly lower PBMCs-DNA methylation than controls [4.39(95%CIs 4.25–4.53) vs. 5.13(95%CIs 5.03–5.21)%mCyt/(mCyt+Cyt), P<0.0001]. A DNA methylation threshold of 4.74% clearly categorized cancer patients from controls so that those with DNA methylation <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 compared to controls [4.34(95%CIs 4.24–4.51) vs. 5.08(95%CIs 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%CIs 1.52–32.63, P=0.013). Genomic PBMCs-DNA methylation may be a useful epigenetic biomarker for early detection and cancer risk estimation. 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.