Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk
Menée à partir d'échantillons sanguins prélevés sur 753 participants (âge moyen : 64 ans), cette étude évalue l'intérêt de mesurer le niveau de méthylation de l'ADN dans les cellules mononucléées du sang périphérique pour la détection précoce d'un cancer ou l'estimation d'un risque de cancer
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 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.
Cancer Epidemiology Biomarkers & Prevention , résumé, 2013