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

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 ¼ 1.64 Â 10 À4 ]. 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. Ó2012 AACR.

LINE1methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US (PLCO) and European (ATBC) cohort study participants

“…Also, a higher ICC was observed in ATBC compared with the PLCO study. Although ICCs are rarely reported, in comparison to Liao et al 19 and a previous study of breast cancer, 21 the ICCs we report are comparatively higher. Strengths of this study include the high quality questionnaire data collected prior to cancer diagnosis, thus reducing the risk of recall bias.…”

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

“…Also, although methylation of LINE-1 repetitive elements has been shown to provide results that parallel those obtained from a direct measurement of genomic DNA methylation, 60 LINE-1 methylation has its limitations as a surrogate measure of genomic methylation and we are not certain that there is a definitive association between percent LINE-1 methylation (in WBCs or breast tissues) and breast cancer risk. 61 Another consideration is that our finding of a lack of a significant association between plasma or breast folate concentrations (which we recently showed are only modestly correlated [r D 0.21, P D 0.07] 52 ) and LINE-1 methylation could be due to measurement error, particularly for the breast folate assay which had a CV >10%. Finally, since there are no known clinically relevant cut-points/thresholds for LINE-1 methylation that are related to breast cancer risk, our findings of 1-4% differences in normal tissues (in association with some factors studied here) might be clinically relevant.…”

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

“…18,19 Nevertheless, the Illumina 27K Array is a limited genome-wide methylation screen. The reported BC-associated altered methylation loci of the ATM gene 16,17 and the differentially methylated DOK7 gene identified in the BC discordant identical twins 12 are not included in the Illumina 27K Array.…”

“…[13][14][15] A few aberrant methylation patterns in peripheral blood have also been reported in BC by candidate gene approaches. [16][17][18][19] Recently, Xu et al reported an extensive blood-based epigenome-wide association study of BC by Illumina 27K Methylation Array in a well-designed prospective sister study cohort, and demonstrated that the methylation profiling of blood are promising markers for BC detection and risk evaluation. 20 Hereby, we conducted an Infinium 27K Methylation Array on peripheral blood DNA in case-control study, and performed further independent validations by MassARRAY for BC-associated methylation variability.…”