title: The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether specific combinations of polymorphisms in 5-fluorouracil (5-FU) metabolism-related genes were associated with outcome in 5-FU-based adjuvant treatment of colorectal cancer.
  
  
  METHODS
  We analyzed two cohorts of 302 and 290 patients, respectively, one cohort for exploratory analyses and another cohort for validating the exploratory analyses. A total of ten polymorphisms in genes involved in 5-FU pharmacodynamics and pharmacokinetics were studied. End points were disease-free survival (DFS) and overall survival. Multifactor dimensionality reduction was used to identify genetic interaction profiles associated with outcome.
  
  
  RESULTS
  Low-expression alleles in thymidylate synthase (TYMS) were associated with decreased DFS and overall survival (DFS:hazard ratio [HR] exploration 2.65 [1.40-4.65]; p = 0.004, HR validation 1.69 [1.03-2.66]; p = 0.03). A specific multifactor dimensionality reduction derived combination of dihydropyrimidine dehydrogenase and TYMS polymorphisms was associated with increased DFS (HR exploration 0.69 [0.49-0.98]; p = 0.04, HR validation 0.66 [0.45-0.95]; p = 0.03). Specific combinations of functional polymorphisms in DPYD and TYMS were demonstrated to be associated with DFS and overall survival in patients receiving adjuvant 5-FU-based treatment. Specifically high TYMS expression alleles seem to be associated with decreased DFS.
authors.affiliation: Rigshospitalet, Copenhagen, Denmark. shoaibafzal@hotmail.com
authors.forename: Shoaib
authors.initials: S
authors.lastname: Afzal
authors.forename: Milena
authors.initials: M
authors.lastname: Gusella
authors.forename: Søren Astrup
authors.initials: SA
authors.lastname: Jensen
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.forename: Jon Trærup
authors.initials: JT
authors.lastname: Andersen
authors.forename: Kasper
authors.initials: K
authors.lastname: Brødbæk
authors.forename: Morten
authors.initials: M
authors.lastname: Petersen
authors.forename: Espen
authors.initials: E
authors.lastname: Jimenez-Solem
authors.forename: Vilmos
authors.initials: V
authors.lastname: Adleff
authors.forename: Barna
authors.initials: B
authors.lastname: Budai
authors.forename: Erika
authors.initials: E
authors.lastname: Hitre
authors.forename: István
authors.initials: I
authors.lastname: Láng
authors.forename: Eniko
authors.initials: E
authors.lastname: Orosz
authors.forename: Laura
authors.initials: L
authors.lastname: Bertolaso
authors.forename: Carmen
authors.initials: C
authors.lastname: Barile
authors.forename: Roberto
authors.initials: R
authors.lastname: Padrini
authors.forename: Judit
authors.initials: J
authors.lastname: Kralovánszky
authors.forename: Felice
authors.initials: F
authors.lastname: Pasini
authors.forename: Henrik Enghusen
authors.initials: HE
authors.lastname: Poulsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil