BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development

PLoS One. 2014 Jun 20;9(6):e100068. doi: 10.1371/journal.pone.0100068. eCollection 2014.

Abstract

The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous) BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Transformation, Viral
  • Gene Expression Profiling*
  • Genes, BRCA1*
  • Genome, Human / genetics
  • Haploinsufficiency*
  • Herpesvirus 4, Human / physiology
  • Heterozygote
  • Humans
  • Interferons / metabolism
  • Lymphocytes / pathology
  • Lymphocytes / virology
  • Transcription, Genetic / genetics

Substances

  • Interferons

Grants and funding

This work was supported by operating funds from the Canadian Breast Cancer Foundation (Ontario Chapter) and the Kingston General Hospital Department of Pathology Clinical Trust Fund to SD and HF, and by infrastructure support through the Canada Foundation for Innovation Leaders Opportunity Fund, and the Ontario Research Fund (SD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.