Abstract LB-275: Identifying novel candidate breast cancer candidate loci by genome-wide allele-specific expression analysis

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 BRCA1/2 can lead to DASE of BRCA1/2 and enhanced susceptibility to breast cancer (BCa). Besides truncation mutations, multiple genetic factors can affect DASE. We identified novel alterations in BRCA1 promoter regions that mediate transcription factor binding thus disrupting mutant BRCA1 allele expression. In addition, we found that mutations in three prime untranslated regions which suppress expression of BRCA1 via modifying miRNA targeting, may be associated with an increased risk of BCa. Therefore, we hypothesize that DASE is a sensitive functional index for genetic variants, and global mapping of DASE in BCa precursor tissue can be used as a new genetic approach to identify risk alleles for BCa suceptibility. To test this hypothesis, we first employed the Illumina® Omni1 array for genome-wide allele-specific expression (GWASE) measurements in a set of eight normal human mammary epithelial lines (HMEC) established from breast cancer patients. A total of 11,954 SNPs at transcribed regions passed expression and genotyping quality filtering in at least three of the eight samples. For data analysis, we applied the empirical Bayes methodology outlined in linear models for microarray data (LIMMA) to identify SNP sites that exhibit at least 2-fold of DASE®. We identified 1,210 SNPs in 1,014 genes with genome-wide significant association to DASE (P < 0.01 and FDR < 10%). By Ingenuity® Pathway analysis, we found the cellular functions of these genes are wide-ranging, including cell signaling, posttranslational modification, DNA Repair, apoptosis, cell proliferation, and lipid metabolism. We next crossed the DASE loci identified in our genome-wide studies with current cancer genome database (Sanger Institute) and identified 12 DASE loci which are listed as cancer genes. Several of these cancer genes present highly significant DASE in our study, such as USP6 (P = 0.00006), PHOX2B (P = 0.0001), SOX2 (P = 0.0002). In summary, this study established a novel approach to searching for breast cancer candidate loci by genome-wide allele-specific profiling, which is a powerful tool in combination with currently available cancer genome databases. This work was supported by the Susan G. Komen for the Cure, KG100274 (XC); and an appropriation from the Commonwealth of Pennsylvania. (®: A DASE event is defined as that the expression level from one allele is at least 50% less than the level of another allele.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-275. doi:10.1158/1538-7445.AM2011-LB-275