title: A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Caronia
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Javier
authors.initials: J
authors.lastname: Sastre
authors.forename: Julio
authors.initials: J
authors.lastname: de la Torre
authors.forename: José Angel
authors.initials: JA
authors.lastname: García-Sáenz
authors.forename: Maria R
authors.initials: MR
authors.lastname: Alonso
authors.forename: Leticia T
authors.initials: LT
authors.lastname: Moreno
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D000069287:Capecitabine; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003564:Cytidine Deaminase / Q000235:genetics*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D050684:E2F Transcription Factors / Q000378:metabolism; D004890:Erythema / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives*; D005533:Foot Dermatoses / Q000139:chemically induced* / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006229:Hand Dermatoses / Q000139:chemically induced* / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000009:adverse effects*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014158:Transcription, Genetic
chemical_list: D000964:Antimetabolites, Antineoplastic; D050684:E2F Transcription Factors; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D003564:Cytidine Deaminase; D005472:Fluorouracil