Breast Cancer Research and Treatment

, Volume 112, Issue 2, pp 229–236

Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers

Authors

  • Logan C. Walker
    • Queensland Institute of Medical ResearchPO Royal Brisbane Hospital
  • Nic Waddell
    • Queensland Institute of Medical ResearchPO Royal Brisbane Hospital
  • Anette Ten Haaf
    • Queensland Institute of Medical ResearchPO Royal Brisbane Hospital
  • kConFab Investigators
    • Peter MacCallum Cancer Centre
  • Sean Grimmond
    • Institute for Molecular BiosciencesUniversity of Queensland
    • Queensland Institute of Medical ResearchPO Royal Brisbane Hospital
Preclinical Study

DOI: 10.1007/s10549-007-9848-5

Cite this article as:
Walker, L.C., Waddell, N., Ten Haaf, A. et al. Breast Cancer Res Treat (2008) 112: 229. doi:10.1007/s10549-007-9848-5

Abstract

Germline mutations in BRCA1 or BRCA2 confer an increased lifetime risk of developing breast or ovarian cancer, but variable penetrance suggests that cancer susceptibility is influenced in part by modifier genes. Microarray expression profiling was conducted for 69 irradiated lymphoblastoid cell lines derived from healthy controls, or from cancer-affected women with a strong family history of breast and ovarian cancer carrying pathogenic mutations in BRCA1 or BRCA2, or with no BRCA1/2 mutations (BRCAX). Genes discriminating between BRCA1, BRCA2 or BRCAX and controls were stratified based on irradiation response and/or cell cycle involvement. Gene lists were aligned against genes tagged with single nucleotide polymorphisms (SNPs) determined by the Cancer Genetic Markers of Susceptibility (CGEMS) Breast Cancer Whole Genome Association Scan to be nominally associated with breast cancer risk. Irradiation responsive genes whose expression correlated with BRCA1 and/or BRCA2 mutation status were more likely to be tagged by risk-associated SNPs in the CGEMS dataset (BRCA1, P = 0.0005; BRCA2, P = 0.01). In contrast, irradiation responsive genes correlating with BRCAX status were not enriched in the CGEMS dataset. Classification of expression data by involvement in cell cycle processes did not enrich for genes tagged by risk-associated SNPs, for BRCA1, BRCA2 or BRCAX groups. Using a novel combinatorial approach, we have identified a subset of irradiation responsive genes as high priority candidate BRCA1/2 modifier genes. Similar approaches may be used to identify genes and underlying genetic risk factors that interact with exogenous stimulants to cause or modify any disease, without a priori knowledge of the pathways involved.

Keywords

BRCA1BRCA2BRCAXBreast cancerCell cycleCancer Genetic Markers of Susceptibilty (CGEMS)IrradiationMicroarrayModifier genes

Supplementary material

10549_2007_9848_MOESM2_ESM.xls (309 kb)
(XLS 309 kb)
10549_2007_9848_MOESM3_ESM.xls (142 kb)
(XLS 142 kb)

Copyright information

© Springer Science+Business Media, LLC. 2007