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DNA Methylation as a Long-term Biomarker of Exposure to Tobacco Smoke

Shenker, Natalie S.a; Ueland, Per Magneb; Polidoro, Silviac; van Veldhoven, Karind; Ricceri, Fulvioc; Brown, Roberta; Flanagan, James M.a; Vineis, Paoloc,d

doi: 10.1097/EDE.0b013e31829d5cb3

Background: Most biomarkers of exposure tend to have short half-lives. This includes cotinine, a metabolite of nicotine widely used to assess smoke exposure. Cotinine is thus unsuitable as a determinant of past exposure to cigarette smoke.

Methods: We used bisulphite pyrosequencing of a set of four genomic loci (AHRR, 6p21, and two at 2q37) that had differential DNA methylation levels in peripheral blood DNA dependent on tobacco exposure to create a predictive model of smoking status.

Results: Combining four gene loci into a single methylation index provided high positive predictive and sensitivity values for predicting former smoking status in both test (n = 81) and validation (n = 180) sample sets.

Conclusions: This study provides a direct molecular measure of prior exposure to tobacco that can be performed using the quantitative approach of bisulphite pyrosequencing. Epigenetic changes that are detectable in blood may more generally act as molecular biomarkers for other exposures that are also difficult to quantify in epidemiological studies.

From the aDepartment of Surgery and Cancer, Epigenetics Unit, Imperial College London, London, United Kingdom; bSection of Pharmacology, Institute of Medicine, University of Bergen, Bergen, Norway; cHuGeF Foundation, Torino, Italy; and dMRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.

J.M.F. is funded by a Breast Cancer Campaign Fellowship. J.M.F. and R.B. acknowledge funding from Cancer Research UK (A13086) and the Imperial Biomedical Research Centre. P.V. is funded by the HuGeF Foundation, Torino, Italy. N.S.S. is funded by a Medical Research Council UK graduate scholarship.

The authors have declared that they have no relationships that could be construed as resulting in an actual, potential or perceived conflict of interest with regard to the article submitted.

Correspondence: James M. Flanagan, Epigenetics Unit, Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London W12 0NN. E-mail:

Received January 11, 2013

Accepted April 5, 2013

© 2013 by Lippincott Williams & Wilkins, Inc