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Br J Cancer. 2016 Aug 9;115(4):465-72. doi: 10.1038/bjc.2016.205. Epub 2016 Jun 28.

Prospective changes in global DNA methylation and cancer incidence and mortality.

Author information

Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA.
Division of Epidemiology/Biostatistics, School of Public Health, University of Illinois-Chicago, 1603 W. Taylor Street, Chicago, IL 60612, USA.
Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA.
Vanderbilt University Medical Center, 2525 West End Avenue, Suite 319, Nashville, TN 37203, USA.
Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, 676 N. St Clair Street, 8th Floor, Chicago, IL 60611, USA.
Department of Medical Oncology, Division of Population Science, Sidney Kimmel Cancer Center, Thomas Jefferson University, 834 Chestnut Street, Suite 314, Philadelphia, PA 19107, USA.
VA Normative Aging Study, VA Boston Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, USA.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Molecular Epidemiology and Environmental Epigenetics Laboratory, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, San Barnaba 8, Milan 20122, Italy.
Department of Environmental Health, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Olson Pavilion 8350, Chicago, IL 60611, USA.



Methylation of repetitive elements Alu and LINE-1 in humans is considered a surrogate for global DNA methylation. Previous studies of blood-measured Alu/LINE-1 and cancer risk are inconsistent.


We studied 1259 prospective methylation measurements from blood drawn 1-4 times from 583 participants from 1999 to 2012. We used Cox regression to evaluate time-dependent methylation as a biomarker for cancer risk and mortality, and linear regression to compare mean differences in methylation over time by cancer status and analyse associations between rate of methylation change and cancer.


Time-dependent LINE-1 methylation was associated with prostate cancer incidence (HR: 1.38, 95% CI: 1.01-1.88) and all-cancer mortality (HR: 1.41, 95% CI: 1.03-1.92). The first measurement of Alu methylation (HR: 1.39, 95% CI: 1.08-1.79) was associated with all-cancer mortality. Participants who ultimately developed cancer had lower mean LINE-1 methylation than cancer-free participants 10+ years pre-diagnosis (P<0.01). Rate of Alu methylation change was associated with all-cancer incidence (HR: 3.62, 95% CI: 1.09-12.10).


Our results add longitudinal data on blood Alu and LINE-1 methylation and cancer, and potentially contribute to their use as early-detection biomarkers. Future larger studies are needed and should account for the interval between blood sample collection and cancer diagnosis.

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