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(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. Results: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 3 concordantly showed a higher prevalence of cancer history (OR=7.04,95%CIs 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.
Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk
FRISO, Simonetta;Udali, Silvia;GUARINI, Patrizia;PATTINI, Patrizia;MORUZZI, Sara;GIRELLI, Domenico;PIZZOLO, Francesca;MARTINELLI, Nicola;CORROCHER, Roberto;OLIVIERI, Oliviero;
2013-01-01
Abstract
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(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. Results: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 3 concordantly showed a higher prevalence of cancer history (OR=7.04,95%CIs 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.
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