Author
FRISO, SIMONETTA - University Of Verona | |
UDALI, SILVIA - University Of Verona | |
GUARINI, PATRIZIA - University Of Verona | |
PELLEGRINI, CAMILLA - University Of Verona | |
PATTINI, PATRIZIA - University Of Verona | |
MORUZZI, SARA - University Of Verona | |
GIRELLI, DOMENICO - University Of Verona | |
PIZZOLO, FRANCESCA - University Of Verona | |
MARTINELLI, NICOLA - University Of Verona | |
CORROCHER, ROBERTO - University Of Verona | |
OLIVIERI, OLIVIERO - University Of Verona | |
CHOI, SANG-WOON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University |
Submitted to: Cancer Epidemiology Biomarkers and Prevention
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 12/11/2012 Publication Date: 1/8/2013 Citation: Friso, S., Udali, S., Guarini, P., Pellegrini, C., Pattini, P., Moruzzi, S., Girelli, D., Pizzolo, F., Martinelli, N., Corrocher, R., Olivieri, O., Choi, S. 2013. Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk. Cancer Epidemiology Biomarkers and Prevention. 22(3):348-355. Interpretive Summary: DNA methylation is a chemical modification of DNA, a nucleic acid that carries the genetic information in the cell. In the present study, we found that the level of DNA methylation in blood cells can be a biomarker to predict the presence or future occurrence of cancer. Interestingly, the levels of blood DNA methylation are highly correlated with blood folate concentrations, a water soluble B vitamin, and a gene associated with folate metabolism. Technical Abstract: 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 (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. 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). 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. |