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Carcinogenesis Advance Access originally published online on July 7, 2009
Carcinogenesis 2009 30(11):1889-1897; doi:10.1093/carcin/bgp143
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Association between global DNA hypomethylation in leukocytes and risk of breast cancer

Ji-Yeob Choi1,2, Smitha R. James3, Petra A. Link3, Susan E. McCann1, Chi-Chen Hong1, Warren Davis1, Mary K. Nesline1, Christine B. Ambrosone1,* and Adam R. Karpf3

1 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
2 Pharmacogenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea
3 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA

* To whom correspondence should be addressed. Tel: +1 716 845 3082; Fax: +1 716 845 8125; Email: chrstine.ambrosone{at}roswellpark.org

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 ≤0.001). Among controls only and cases and controls combined, only alcohol intake was found to be inversely associated with methylation levels. Conclusion: These findings suggest that leukocyte DNA hypomethylation is independently associated with development of breast cancer.

Abbreviations: CI, confidence interval; DBBR, Databank and Biorepository; 5-mdC, 5-methyldeoxycytosine; OR, odds ratio; RPCI, Roswell Park Cancer Institute

Received April 11, 2009; revised May 21, 2009; accepted May 28, 2009.


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