Abstract 1881: Integration of cell line and Cancer and Leukemia Group B 40101 clinical trial genome-wide association analyses implicates multiple loci in paclitaxel-induced peripheral neuropathy

Background: Paclitaxel is a microtubule-stabilizing chemotherapy drug often used in the treatment of breast, ovarian and lung cancers. Together, these three types comprised 47% of new cancers in American females in 2011. However, variable drug resistance and toxicities among individuals limit successful outcomes. The goal of chemotherapeutic pharmacogenomics research is to predict which patients may have greater risk for either drug resistance or dose-limiting toxicities based on their genotypes. Methods: We used lymphoblastoid cell lines (LCLs) derived from HapMap YRI (Yoruba), ASW (African Americans) and CEU (Northern and Western European ancestry) populations to measure paclitaxel-induced cytotoxicity. Using publicly available genotype data, we have performed a genome-wide association study (GWAS) for paclitaxel-induced cytotoxicity in these three populations. To better understand the relevance of our LCL model in terms of clinical paclitaxel-induced toxicity, we compared our results to a GWAS of peripheral sensory neuropathy in breast cancer patients (n=855) treated with paclitaxel from the CALGB 40101 clinical trial. The cumulative paclitaxel dose triggering a grade 2 or higher sensory peripheral neuropathy event (24% of patients) was the phenotype used in the clinical GWAS. Results: We observed an enrichment of cytotoxicity-associated SNPs in the peripheral neuropathy-associated SNPs from the clinical trial (empirical p = 4 x 10 −3 ). Of the 36 SNPs that overlap between the clinical trial (p −3 ), 29 of them are expression quantitative trait loci (eQTLs), which is a significant enrichment of this functional class (empirical p = 8 x 10 −3 ). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family (cytotoxicity p = 5.9 x 10 −4 , clinical trial p = 4.8 x 10 −2 ). Decreased expression of this gene by siRNA resulted in increased sensitivity of NS-1 (rat pheochromocytoma) cells to paclitaxel measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in paclitaxel sensitivity. Conclusions: Our integrative approach combining a clinical GWAS and a cell-based GWAS followed by functional studies provides a framework for prioritizing SNPs involved in drug response and, in this study, lends support for the involvement of RFX2 in patient response to paclitaxel. These results demonstrate the importance of eQTLs in chemotherapeutic-induced toxicities. If these particular findings are replicated in additional cohorts, the ability to identify patients at risk of paclitaxel-induced peripheral neuropathy could influence treatment choice, outcome and quality of life for breast, ovarian and lung cancer patients. This work was supported in part by NIH/NIGMS UO1GM61393 and U01GM61390. 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 1881. doi:1538-7445.AM2012-1881