title: Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk.
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 (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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. simonetta.friso@univr.it
authors.forename: Simonetta
authors.initials: S
authors.lastname: Friso
authors.forename: Silvia
authors.initials: S
authors.lastname: Udali
authors.forename: Patrizia
authors.initials: P
authors.lastname: Guarini
authors.forename: Camilla
authors.initials: C
authors.lastname: Pellegrini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pattini
authors.forename: Sara
authors.initials: S
authors.lastname: Moruzzi
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Pizzolo
authors.forename: Nicola
authors.initials: N
authors.lastname: Martinelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Corrocher
authors.forename: Oliviero
authors.initials: O
authors.lastname: Olivieri
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000097:blood; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D014408:Biomarkers, Tumor; D004247:DNA; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)