title: 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 = 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.
authors.affiliation: Epigenetics Unit, Department of Surgery and Cancer, Imperial College, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Brennan
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Nick
authors.initials: N
authors.lastname: Orr
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Anthony
authors.initials: A
authors.lastname: Swerdlow
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Miren
authors.initials: M
authors.lastname: Dorronsoro
authors.forename: Francoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: N Charlotte
authors.initials: NC
authors.lastname: Onland-Moret
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.forename: James M
authors.initials: JM
authors.lastname: Flanagan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases