Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk

Kevin Brennan, Montserrat Garcia-Closas, Nick Orr, Olivia Fletcher, Michael Jones, Alan Ashworth, Anthony Swerdlow, Heather Thorne, Elio Riboli, Paolo Vineis, Miren Dorronsoro, Francoise Clavel-Chapelon, Salvatore Panico, N Charlotte Onland-Moret, Dimitrios Trichopoulos, Rudolf Kaaks, Kay-Tee Khaw, Robert Brown, James M Flanagan, KConFab Investigators

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105 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2304-13
Number of pages10
JournalCancer Research
Volume72
Issue number9
DOIs
Publication statusPublished - 01 May 2012

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Ataxia Telangiectasia Mutated Proteins
  • Australia
  • Breast Neoplasms
  • Case-Control Studies
  • Cell Cycle Proteins
  • DNA Methylation
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Europe
  • Female
  • Humans
  • Leukocytes
  • Middle Aged
  • New Zealand
  • Protein-Serine-Threonine Kinases
  • Tumor Suppressor Proteins
  • United Kingdom
  • Young Adult
  • Journal Article
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Brennan, K., Garcia-Closas, M., Orr, N., Fletcher, O., Jones, M., Ashworth, A., Swerdlow, A., Thorne, H., Riboli, E., Vineis, P., Dorronsoro, M., Clavel-Chapelon, F., Panico, S., Onland-Moret, N. C., Trichopoulos, D., Kaaks, R., Khaw, K-T., Brown, R., Flanagan, J. M., & KConFab Investigators (2012). Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Research, 72(9), 2304-13. https://doi.org/10.1158/0008-5472.CAN-11-3157