Levels of DNA Methylation Vary at CpG Sites across the BRCA1 Promoter, and Differ According to Triple Negative and "BRCA-Like" Status, in Both Blood and Tumour DNA

PLoS One. 2016 Jul 27;11(7):e0160174. doi: 10.1371/journal.pone.0160174. eCollection 2016.

Abstract

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • BRCA1 Protein / genetics*
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • CpG Islands
  • DNA Methylation*
  • DNA, Neoplasm / blood
  • DNA, Neoplasm / genetics
  • Female
  • Humans
  • Middle Aged
  • Promoter Regions, Genetic
  • Triple Negative Breast Neoplasms / blood
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Biomarkers, Tumor
  • DNA, Neoplasm

Grants and funding

Cancer Research UK (CRUK) provided funding for this project in the form of a Research Bursary: Career and Development Fund ref C47655/A16817 www.cruk.org SLD IWB LW AC. The National Institute for Health Research (NIHR) provided salary contribution for SLD via an Academic Clinical Fellowship www.nihr.ac.uk. The Sheffield Experimental Cancer Medicine Centre provided a research grant www.sheffield.ac.uk to SLD LW AC. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.