Global DNA hypomethylation in liver cancer cases and controls: a phase I preclinical biomarker development study.
BACKGROUND
Global genomic DNA hypomethylation is a feature of genomic DNA derived from solid and hematologic tumors in animal models and human carcinogenesis. Global genomic DNA hypomethylation may be the earliest epigenetic change from a normal to a pre-malignant cell.


OBJECTIVE
To test if global hypomethylation is a good marker for early detection of cancer we used a novel quantification method of 2'-deoxynucleosides to evaluate DNA methylation in liver cancer cases and controls.


METHODS
Frozen tissue from liver cancer patients and controls were obtained from the Cooperative Human Tissue Network. DNA was extracted using standard methods. Genomic DNA samples were boiled and treated with nuclease P1 and alkaline phosphatase. Global genomic DNA methylation patterns were obtained using HPLC for fraction separation and mass spectrometry for quantification. A two-sample t-test was performed using Welch's approximation for samples with unequal variances. A Wilcoxon rank sum test was also performed.


RESULTS
A global genomic DNA methylation index measuring methylated cytidine relative to global cytidine in the genome was significantly lower (p value = 0.001) for all cases, mean = 2.43 (95% CI, 2.08, 2.78), when compared to controls, mean = 3.55 (95% CI, 3.16, 3.93).


CONCLUSIONS
A correlation between global genomic DNA methylation patterns and type of liver tissue was observed. These results add to the accumulating body of evidence suggesting that global DNA hypomethylation may be a useful biomarker to distinguish between liver cancer cases and controls.
Guerrero-Preston
Rafael
R
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA. rguerre3@jhmi.edu
Santella
Regina M
RM
Blanco
Adolfo
A
Desai
Manisha
M
Berdasco
Maria
M
Fraga
Mario
M
D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D019175:DNA Methylation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D021241:Spectrometry, Mass, Electrospray Ionization
D014408:Biomarkers, Tumor