Epigenome-wide association study of breast cancer using prospectively collected sister study samples

J Natl Cancer Inst. 2013 May 15;105(10):694-700. doi: 10.1093/jnci/djt045. Epub 2013 Apr 11.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / genetics
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / ethnology
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Cycle Proteins / genetics
  • Checkpoint Kinase 2
  • Chromosomal Proteins, Non-Histone / genetics
  • CpG Islands* / genetics
  • DNA Methylation* / genetics
  • DNA-Binding Proteins / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins / genetics
  • PTEN Phosphohydrolase / genetics
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Prospective Studies
  • Protein-Serine-Threonine Kinases / genetics
  • ROC Curve
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Reproductive History
  • Risk Assessment
  • Risk Factors
  • Sampling Studies
  • Siblings*
  • Tumor Suppressor Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • BRCA1 protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • LRATD1 protein, human
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • spermatid transition proteins
  • Checkpoint Kinase 2
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein