Data from Integration of Cell Line and Clinical Trial Genome-Wide Analyses Supports a Polygenic Architecture of Paclitaxel-Induced Sensory Peripheral Neuropathy

Abstract

<div>Abstract<p><b>Purpose:</b> We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results.</p><p><b>Experimental Design:</b> A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (<i>n</i> = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis.</p><p><b>Results:</b> We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical <i>P</i> = 0.007). Of the 24 SNPs that overlap between the clinical trial (<i>P</i> < 0.05) and the preclinical cytotoxicity study (<i>P</i> < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical <i>P</i> = 0.0447). One of these eQTLs is located in <i>RFX2</i>, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of <i>RFX2</i> in nerve cell response to paclitaxel.</p><p><b>Conclusions:</b> The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients. <i>Clin Cancer Res; 19(2); 491–9. ©2012 AACR</i>.</p></div>