부산대학교 도서관

Byline: Logan C. Walker (1), Nic Waddell (1), Anette Ten Haaf (1), Sean Grimmond (3), Amanda B. Spurdle (1) Keywords: BRCA1; BRCA2; BRCAX; Breast cancer; Cell cycle; Cancer Genetic Markers of Susceptibilty (CGEMS); Irradiation; Microarray; Modifier genes 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. Author Affiliation: (1) Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, QLD, 4029, Australia (2) Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia (3) Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia Article History: Registration Date: 30/11/2007 Received Date: 29/11/2007 Accepted Date: 30/11/2007 Online Date: 20/12/2007 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s10549-007-9848-5) contains supplementary material, which is available to authorized users.