Abstract 1875: Identifying genetic variants contributing to cellular susceptibility to tamoxifen using a genome-wide cell-based model

Abstract

Abstract Tamoxifen is one of the most commonly used agents in the treatment and prevention of estrogen receptor positive breast cancers. Beyond the presence of hormone receptors, there are no validated predictors of tamoxifen efficacy and toxicity. Therefore, we utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular susceptibility to tamoxifen. Our model incorporates multi-dimensional datasets including genome-wide genotype, gene expression, and cellular growth inhibition following treatment in lymphoblastoid cell lines from the International HapMap project. Growth inhibition was measured using AlamarBlue Assay in 60 unrelated CEU (individuals of northern and western European decedent) and 60 unrelated YRI (individuals from Ibadan, Nigeria) samples. All cell lines were treated with increasing concentrations of endoxifen, an active metabolite of tamoxifen, for 72 hours. Log2 transformed percent survival at each concentration and IC50 were used as cellular susceptibility to drug phenotypes. A step-wise genome-wide association studies were performed among SNPs, mRNA expression, and endoxifen sensitivity phenotypes. We identified 10 and 74 SNPs associated with endoxifen sensitivity through the expression of 13 and 92 genes in the separate CEU and YRI population. Interestingly 3 genes (STS, TES and SMARCA2) identified through this method are known to play a role in hormone biosynthesis pathway. Furthermore, a large portion of identified genes was found to play a role in tamoxifen sensitivity in the NCI60 cancer cell lines including CHPT1, a known tumor progression marker. This approach has made possible the identification of genetic variants/genes that have not been previously associated with tamoxifen response. Further validation of these cell-based model findings may significantly improve our ability to predict tamoxifen treatment efficacy and toxicity in breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1875. doi:1538-7445.AM2012-1875