Association between global DNA hypomethylation in leukocytes and risk of breast cancer.
BACKGROUND
Global DNA hypomethylation may result in chromosomal instability and oncogene activation, and as a surrogate of systemic methylation activity, may be associated with breast cancer risk.


METHODS
Samples and data were obtained from women with incident early-stage breast cancer (I-IIIa) and women who were cancer free, frequency matched on age and race. In preliminary analyses, genomic methylation of leukocyte DNA was determined by measuring 5-methyldeoxycytosine (5-mdC), as well as methylation analysis of the LINE-1-repetitive DNA element. Further analyses used only 5-mdC levels. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of breast cancer in relation to amounts of methylation.


RESULTS
In a subset of samples tested (n = 37), 5-mdC level was not correlated with LINE-1 methylation. 5-mdC level in leukocyte DNA was significantly lower in breast cancer cases than healthy controls (P = 0.001), but no significant case-control differences were observed with LINE-1 methylation (P = 0.176). In the entire data set, we noted significant differences in 5-mdC levels in leukocytes between cases (n = 176) and controls (n = 173); P value < 0.001. Compared with women in the highest 5-mdC tertile (T3), women in the second (T2; OR = 1.49, 95% CI = 0.84-2.65) and lowest tertile (T1; OR = 2.86, 95% CI = 1.65-4.94) had higher risk of breast cancer (P for trend < or = 0.001). Among controls only and cases and controls combined, only alcohol intake was found to be inversely associated with methylation levels.


CONCLUSIONS
These findings suggest that leukocyte DNA hypomethylation is independently associated with development of breast cancer.
Choi
Ji-Yeob
JY
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
James
Smitha R
SR
Link
Petra A
PA
McCann
Susan E
SE
Hong
Chi-Chen
CC
Davis
Warren
W
Nesline
Mary K
MK
Ambrosone
Christine B
CB
Karpf
Adam R
AR
D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D016001:Confidence Intervals; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D012091:Repetitive Sequences, Nucleic Acid; D012306:Risk; D012307:Risk Factors; D012907:Smoking
C065701:5-methyldeoxycytosine; D004273:DNA, Neoplasm; D044503:5-Methylcytosine