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Proffered Abstract (Plenary Session): Germline Determinants of Therapeutic Efficacy and Toxicity

Genes contributing to etoposide-induced cytotoxicity

University of Chicago, Chicago, IL

Abstract

PR-3

Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. The degree to which genetic factors contribute to susceptibility to etoposide is not fully understood. We present a comprehensive genetic method that incorporates whole genome association analysis and bioinformatics to uncover genetic variants contributing to susceptibility to etoposide-induced cytotoxicity. EBV-transformed lymphoblastoid cell lines representing 30 trios of European descent and 30 trios of Yoruban descent from the International HapMap consortium were assayed for cell growth inhibition following incubation with increasing concentrations of etoposide for 72 h. Whole genome association with one-way ANOVA test was independently performed on the 60 unrelated CEPH and Yoruban cell lines. Several pathways emerged in each population with the most significant being calcium signaling pathway in both. Two genes within the calcium signaling pathway had single nucleotide polymorphisms (SNPs) significantly associated with etoposide cytotoxicity in both populations; CACNA1C a subunit of a voltage-dependent calcium channel and HDAC9, a histone deacetylase. A total of 5 SNPs and 33 SNPs were significant after additive model linear regression analysis for CACNA1C in the CEPH and Yoruban population; 14 SNPs were significant for HDAC9 in the Yoruban population. This novel method can be used to elucidate variants contributing to chemotherapeutic response.