%0 Journal Article
%T Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines
%A Lawson Eng
%A Irada Ibrahim-zada
%A Hamdi Jarjanazi
%A Sevtap Savas
%A Mehran Meschian
%A Kathleen I Pritchard
%A Hilmi Ozcelik
%J BMC Medical Genomics
%D 2011
%I BioMed Central
%R 10.1186/1755-8794-4-18
%X 43 SNPs were found significantly associated (FDR < 0.005) with paclitaxel response, with 10 belonging to protein-coding genes (CFTR, ROBO1, PTPRD, BTBD12, DCT, SNTG1, SGCD, LPHN2, GRIK1, ZNF607). SNPs in GRIK1, DCT, SGCD and CFTR were predicted to be intronic enhancers, altering gene expression, while SNPs in ZNF607 and BTBD12 cause conservative missense mutations. mRNA expression analysis supported these findings as GRIK1, DCT, SNTG1, SGCD and CFTR showed significantly (p < 0.05) increased expression among sensitive cell lines. Haplotypes found in GRIK1, SGCD, ROBO1, LPHN2, and PTPRD were more strongly associated with response than their individual SNPs.Our study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel.Since its approval by the Food and Drug Administration in 1992, paclitaxel (Taxol, Bristol-Myers Squibb, NY) has been commonly used to treat both breast and ovarian cancers. Paclitaxel has also been used in treatment regimens for head and neck cancers, lung cancers, esophageal cancers, testicular cancers and sarcomas [1-4].Paclitaxel belongs to a family of microtubule-targeting drugs called the taxanes [4]. However, unlike other microtubule-targeting drugs, which cause microtubule instability, paclitaxel stabilizes microtubules leading to the disruption of mitosis (G2/M cell-cycle arrest) and alterati
%U http://www.biomedcentral.com/1755-8794/4/18