Genome-wide DNA Methylation Markers Of Lifestyle Exposure And Pre-Diagnostic Breast Cancer Risk

Srikant AMBATIPUDI, International Agency for Research on Cancer, France
HORVATH S. 2 , PERRIER F. 1 , CUENIN C. 1 , HERNANDEZ-VARGAS H. 1 , GHANTOUS A. 1 , BOUAOUN L. 1 , BYRNES G. 1 , LE CALVEZ-KELM F. 1 , EPIC WORKING GROUP E. 3 , ROMIEU I. 1 , HERCEG Z. 1

1 International Agency for Research on Cancer (IARC), Lyon, France
2 Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA90095, USA
3 EPIC working Group, International Agency for Research on Cancer (IARC), Lyon, France

Purpose
Identifying potential of DNA methylation changes in peripheral blood as a marker of lifestyle exposure and cancer risk is gaining importance. In the present study we assessed whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated smoking status and with increased risk of breast cancer.
Methods
The study cohort included 470 female incident breast cancer cases and matched controls embedded in a large nested case–control cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. DNA methylation levels were measured across 485,777 CpG sites using the Infinium HumanMethylation450 BeadChip kit. The bioinformatics and biostatical analyses were performed using R (version 3.2.2)/Bioconductor packages.
Results
We identified 748 CpG sites and 8 regions that were differentially methylated in smokers compared to non-smokers (FDR ≤ 0.05). We observed a marked reversibility of methylation changes after smoking cessation, although 4 CpG sites in 2 genes (ALPPL2 and AHRR) remained differentially methylated up to 22 years after smoking cessation.
Higher epigenome-wide methylation at CpG island was associated with risk of breast cancer (OR per 1 SD =1.20, 95 % CI: 1.03-1.40). We examined whether epigenetic age acceleration (EAA) which refers to epigenetic age acceleration adjusted for abundance measures of blood cell counts predicts development of breast cancer.  EAA was found to be a significant prognosticator of breast cancer incidence (P = 0.041) at the time of the blood draw. The result becomes even more significant when restricting the analysis to subjects that developed breast cancer within 10 years of follow up (P=0.013).
Conclusions:
Thus, our study demonstrates that prospectively collected blood based DNA methylome changes may serve as potential markers of lifestyle exposure and breast cancer risk.
 
Funding source:
INCa, France, Fondation ARC pour la Recherche sur le Cancer and the EC FP7 EurocanPlatform