Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk.

Source

Authors' Affiliations: Epigenetics Unit, Department of Surgery and Cancer, MRC-HPA Centre, School of Public Health, Imperial College; Breakthrough Breast Cancer Research Centre, Section of Medicine, Institute for Cancer Research, London; Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom; Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; HuGeF Foundation, Torino, Italy; Public Health Division of Gipuzkoa, IIS Institute BioDonostia, Basque Health Department; CIBER Epidemiología y Salud Pública, CIBERESP, Gipuzkoa, Spain; INSERM, Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, University Paris-Sud, Paris, France; Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Hellenic Health Foundation, Athens, Greece; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; and Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.

Abstract

Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood samples from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. Samples were from a case-control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case-control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89; 95% confidence interval (CI), 1.36-2.64; P = 1.64 × 10(-4)]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and individually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation. Cancer Res; 72(9); 2304-13. ©2012 AACR.