title: Epigenome-wide association study of breast cancer using prospectively collected sister study samples.
abstract: BACKGROUND
  Previous studies have suggested DNA methylation in blood is a potential epigenetic marker of cancer risk, but this has not been evaluated on a genome-wide scale in prospective studies for breast cancer.
  
  
  METHODS
  We measured DNA methylation at 27578 CpGs in blood samples from 298 women who developed breast cancer 0 to 5 years after enrollment in the Sister Study cohort and compared them with a random sample of 612 cohort women who remained cancer free. We also genotyped women for nine common polymorphisms associated with breast cancer.
  
  
  RESULTS
  We identified 250 differentially methylated CpGs (dmCpGs) between case subjects and noncase subjects (false discovery rate [FDR] Q < 0.05). Of these dmCpGs, 75.2% were undermethylated in case subjects relative to noncase subjects. Women diagnosed within 1 year of blood draw had small but consistently greater divergence from noncase subjects than did women diagnosed at more than 1 year. Gene set enrichment analysis identified Kyoto Encyclopedia of Genes and Genomes cancer pathways at the recommended FDR of Q less than 0.25. Receiver operating characteristic analysis estimated a prediction accuracy of 65.8% (95% confidence interval = 61.0% to 70.5%) for methylation, compared with 56.0% for the Gail model and 58.8% for genome-wide association study polymorphisms. The prediction accuracy of just five dmCpGs (64.1%) was almost as good as the larger panel and was similar (63.1%) when replicated in a small sample of 81 women with diverse ethnic backgrounds.
  
  
  CONCLUSIONS
  Methylation profiling of blood holds promise for breast cancer detection and risk prediction.
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Zongli
authors.initials: Z
authors.lastname: Xu
authors.forename: Sophia C E
authors.initials: SC
authors.lastname: Bolick
authors.forename: Lisa A
authors.initials: LA
authors.lastname: DeRoo
authors.forename: Clarice R
authors.initials: CR
authors.lastname: Weinberg
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012372:ROC Curve; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D017584:Reproductive History; D018570:Risk Assessment; D012307:Risk Factors; D012494:Sampling Studies; D035781:Siblings; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C515422:LRATD1 protein, human; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C053886:spermatid transition proteins; D064447:Checkpoint Kinase 2; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein