Abstract P3-08-03: Defects in BRCA1 Contribute to Global Differential Allele-Specific Expression

Abstract

Abstract Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variability in humans and more recently to the pathogenesis of cancer. DASE is associated with X-chromosome inactivation and genomic imprinting and is relatively common among non-imprinted autosomal genes. The DASE phenotype can also be transmitted by Mendelian inheritance. We have previously reported that nonsense-mediated mRNA decay (NMD) of mutant BRCA1 as well as other epigenetic mechanisms can lead to DASE of BRCA1 and enhanced susceptibility to breast cancer. BRCA1 has been implicated in many cellular processes including DNA repair, cell-cycle-checkpoint control, protein ubiquitination, and chromatin remodeling. Importantly, cells carrying a deleterious BRCA1 mutation exhibit increased genome instability, therefore, we hypothesize that defects in BRCA1 lead not only to DASE of itself, but increase genome-wide DASE and thus contribute to increased breast cancer susceptibility. To test this hypothesis, we employed a genome-wide ASE assay (Illumina Human Omni1-Quad BeadChip) using primary mammary epithelial cells [3 BRCA1 wild-type vs. 3 BRCA1 mutant carrying (2800delAA, 4154delA and R1751X)]. As shown in Table 1, cells carrying a BRCA1 mutation had significantly more DASE events as compared to wild-type cell (P<10-7). In addition, we identified 351 genes demonstrating DASE that were unique to the BRCA1 mutant cells. The cellular functions of these genes are wideranging, including DNA repair, cell cycle control, lipid metabolism and protein degradation. In summary, this study provides the first evidence that mutant BRCA1 can lead to global DASE, which in turn may contribute to the development of breast cancer in mutation carriers. This work was supported in part by the Eileen Stein-Jacoby Fund and a grant from the Congressionally Directed Medical Research Programs, Department of Defense, W81XWH-08-1-0361 (XC). Table 1. BRCA1 mutations increase the global DASE in PMECs t; A DASE event is defined as that the Log-ratio of allele-specific expression level of one gene is more than 1 or less than -1, i.e. the expression level from one allele is at least 50% less than the level of another allele Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-08-03.