title: Identification of genetic variants associated with capecitabine-induced hand-foot syndrome through integration of patient and cell line genomic analyses.
abstract: OBJECTIVE
  A primary challenge in identifying replicable pharmacogenomic markers from clinical genomewide association study (GWAS) trials in oncology is the difficulty in 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 study and a clinical study on capecitabine is more than expected by chance. A GWAS of capecitabine-induced cytotoxicity was performed in 164 lymphoblastoid cell lines derived from the CEU HapMap population and compared with a GWAS of hand-foot syndrome (HFS), the most frequent capecitabine-induced adverse drug reaction, in Spanish breast and colorectal cancer patients (n=160) treated with capecitabine.
  
  
  RESULTS
  We observed an overlap of 16 single nucleotide polymorphisms associated with capecitabine-induced cytotoxicity (P<0.001) in lymphoblastoid cell lines 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 single nucleotide polymorphisms, which cover the overlap loci, were genotyped in a second patient cohort (n=85) and one of them, rs9936750, was 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.
authors.affiliation: aSection of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA bHuman Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Center cSan Carlos University Hospital dInstitute for Health Research, University Hospital Gregorio Marañón, Madrid eUniversity Hospital Virgen de la Victoria, Malaga, Spain.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Julio-Cesar
authors.initials: JC
authors.lastname: de la Torre-Montero
authors.forename: Rosario
authors.initials: R
authors.lastname: Alonso
authors.forename: Luis A
authors.initials: LA
authors.lastname: Lopez-Fernandez
authors.forename: Emilio
authors.initials: E
authors.lastname: Alba
authors.forename: Miguel
authors.initials: M
authors.lastname: Martín
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000069287:Capecitabine; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D023281:Genomics; D060831:Hand-Foot Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil