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
Autor: | Anette Ten Haaf, kConFab Investigators, Amanda B. Spurdle, Logan C. Walker, Sean M. Grimmond, Nic Waddell |
---|---|
Rok vydání: | 2007 |
Předmět: |
Heterozygote
Cancer Research endocrine system diseases Tumor suppressor gene Genes BRCA2 Genes BRCA1 Breast Neoplasms Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Germline mutation Breast cancer Risk Factors Cell Line Tumor medicine Humans Genetic Predisposition to Disease skin and connective tissue diseases Oligonucleotide Array Sequence Analysis Genetic testing Genetics medicine.diagnostic_test Genome Human Gene Expression Profiling Cancer medicine.disease Gene Expression Regulation Neoplastic Gene expression profiling Oncology Mutation Cancer research Female Breast disease |
Zdroj: | Breast Cancer Research and Treatment. 112:229-236 |
ISSN: | 1573-7217 0167-6806 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |