Abstract 3636: Systems biology approach links genetic, epigenetic, and transcriptomic features to tamoxifen sensitivity.

Abstract

Abstract Utilizing existing genome-wide genotype, transcriptome and microRNA (miRNA) datasets, we developed an integrative approach to evaluate the role of genetic-epigenetic regulatory networks in human complex traits. In this study, we focused on cellular sensitivity to tamoxifen, a commonly prescribed breast cancer medication as a phenotype of interest. A sequential multi-dimensional model was constructed to first identify genes/miRNAs whose expression levels are correlated with tamoxifen sensitivity. This in turn facilitated the identification of SNPs associated with potential functionally relevant genomic features. Finally, associations between these selected SNPs and cellular sensitivity to tamoxifen were evaluated. A permutation-based false discovery rate (FDR) procedure showed that association findings from our approach have much lower FDRs when compared to those obtained through a traditional single-step genome-wide association study (GWAS) between SNP and drug sensitivity. Our model identified 50 unique SNPs associated with 30 miRNAs and 34 gene expression levels, all of which associated with cellular sensitivity to tamoxifen phenotypes in HapMap YRI samples. Among them, several miRNAs and genes have been previously implicated to play a role in tamoxifen sensitivity; most are novel. Functional studies on select miRNAs/genes are currently underway in both the HapMap samples and breast cancer cell lines. Citation Format: Eric R. Gamazon, Liming Weng, Hae Kyung Im, Xiaotong Zhang, Dana M. Ziliak, R. Stephanie Huang. Systems biology approach links genetic, epigenetic, and transcriptomic features to tamoxifen sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2013-3636