Identification of genetic variants associated with capecitabine-induced hand-foot syndrome through integration of patient and cell line genomic analyses.

Abstract

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Objective A primary challenge in identifying replicable pharmacogenomic markers from clinical genome wide association study (GWAS) trials in oncology is the difficulty of performing a second large clinical trial with the same drugs and dosage regimen. We sought to overcome this challenge by incorporating GWAS results from cell-based studies using the same chemotherapy as a clinical cohort. Methods In this study, we test whether the overlap between genetic variants identified in a preclinical and clinical study of capecitabine is more than expected by chance. A GWAS of capecitabine-induced cytotoxicity was performed in 164 lymphoblastoid cell lines (LCLs) derived from the CEU HapMap population and compared to a GWAS of hand-foot syndrome (HFS), the most frequent capecitabine-induced adverse drug reaction (ADR), in Spanish breast and colorectal cancer patients (n=160) treated with capecitabine. Results We observed an overlap of 16 single nucleotide polymorphisms (SNPs) associated with capecitabine-induced cytotoxicity (P < 0.001) in LCLs and HFS (P < 0.05) in patients, which is a greater overlap than expected by chance (genotype-phenotype permutation empirical P = 0.015). Ten tag SNPs, which cover the overlap loci, were genotyped in a second patient cohort (n=85) and one of them, rs9936750, associated with capecitabine-induced HFS (P = 0.0076).Conclusions The enrichment results imply that cellular models of capecitabine-induced cytotoxicity may capture components of the underlying polygenic architecture of related toxicities in patients.