Prioritizing Candidate Genetic Modifiers of BRCA1 and BRCA2 Using a Combinatorial Analysis of Global Expression and Polymorphism Association Studies of Breast Cancer
Epidemiological evidence from different studies has shown that genes harboring sequence variations may modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene-based approach or the development of large genome-wide association studies. However, both methods have notable limitations. This chapter describes a novel approach for analyzing gene expression differences to prioritize candidate modifier genes for single nucleotide polymorphism association studies. The advantage that gives this strategy an edge over other candidate gene-based studies is its potential to identify candidate genes that interact with exogenous risk factors to cause or modify cancer, without detailed a priori knowledge of the molecular pathways involved.
Key wordsFamilial Breast cancer BRCA1 BRCA2 Genetic modifiers Microarray Irradiation Genome wide association study Lymphoblastoid cell lines
We thank Nic Waddell, Anette Ten Haaf, Georgia Chenevix-Trench, Denis Moss and kConFab for their contribution in developing the protocols described here. We also thank Nic Waddell for critical reading of the manuscript. This work was supported by the Susan G. Komen Breast Cancer Foundation and the NHMRC.
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