A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 ( CES2 ) gene, the cytidine deaminase ( CDD ) gene, the thymidine phosphorylase ( TP ) gene, the thymidylate synthase ( TS ) gene, and the dihydropyrimidine dehydrogenase ( DPD ) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02–3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 ( D ′ = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27–0.95, P = 0.028) in patients and with total CDD gene expression ( P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. Conclusions: The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS. Clin Cancer Res; 17(7); 2006–13. ©2011 AACR .