Identifying Genetic Factors Affecting Anthracycline-Induced Cytotoxcity

The molecular mechanisms responsible for anthracycline-induced cytotoxicity have been elusive despite intensive research over the past half century. Here, hits from a genome-wide association (GWA) screen seeking to identify genetic factors influencing drug-dose response were validated using a shRNA approach. The initial screen examined the phenotypic response of over 500 CHORI patient lymphoblastoid cell lines (LCLs) to the anthracyclines daunorubicin, epirubicin, and doxorubicin. Five candidate genes were identified from statistical correlation between intrinsic genomic differences and phenotype variability across the population of cell lines. Of the 5 candidates selected (ADTRP, CSMD3, FHIT, PELI2, and SLC24A3), stable knockdown of PELI2 (and the positive control TOP2A) in LCLs were shown to have a significant effect on dose-dependent anthracycline response. While TOP2A has been previously established in the mechanism of anthracycline response, the identification of PELI2 in this screen is intriguing given recent work implicating NF-κβ; signaling pathways in anthracycline response. These results establish shRNA-mediated gene-knockdown as a means to further validate GWA screens in LCLs.Master of Scienc