title: Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy-treated colorectal cancer patients.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether specific combinations of polymorphisms in genes encoding proteins involved in 5-fluorouracil (5-FU) pharmacokinetics and pharmacodynamics are associated with increased risk of treatment-induced toxicity.
  
  
  METHODS
  We analyzed two cohorts of 161 and 340 patients, the exploration and validation cohort, respectively. All patients were treated similarly with 5-FU-based adjuvant chemotherapy. We analyzed 13 functional polymorphisms and applied a four-fold analysis strategy using individual polymorphisms, haplotypes, and phenotypic enzyme activity or expression classifications based on combinations of functional polymorphisms in specific genes. Furthermore, multifactor dimensionality reduction analysis was used to identify a genetic interaction profile indicating an increased risk of toxicity.
  
  
  RESULTS
  Alleles associated with low activity of methylene tetrahydrofolate reductase (MTHFR) were associated with decreased risk of toxicity [OR(Exploration) 0.39 (95% CI: 0.21-0.71, P = 0.003), OR(Validation) 0.63 (95% CI: 0.41-0.95, P = 0.03)]. A specific combination of the MTHFR 1298A>C and thymidylate synthase (TYMS) 3'-UTR (untranslated region) ins/del polymorphisms was significantly associated with increased toxicity in both cohorts [OR(Exploration) 2.40 (95% CI: 1.33-4.29, P = 0.003), OR(Validation) 1.81 (95% CI: 1.18-2.79, P = 0.007)]. The specific combination was also associated with increased cumulative incidence and earlier occurrence of severe toxicity during treatment.
  
  
  CONCLUSIONS
  Our results indicate that MTHFR activity and a specific combination of the MTHFR 1298A>C and TYMS 3'-UTR ins/del polymorphisms are possible predictors of 5-FU treatment-related toxicity.
authors.affiliation: Laboratory of Clinical Pharmacology, Departments of Pathology and Oncology, 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: Ben
authors.initials: B
authors.lastname: Vainer
authors.forename: Ulla B
authors.initials: UB
authors.lastname: Vogel
authors.forename: Jon T
authors.initials: JT
authors.lastname: Andersen
authors.forename: Kasper
authors.initials: K
authors.lastname: Broedbaek
authors.forename: Morten
authors.initials: M
authors.lastname: Petersen
authors.forename: Espen
authors.initials: E
authors.lastname: Jimenez-Solem
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: Felice
authors.initials: F
authors.lastname: Pasini
authors.forename: Søren A
authors.initials: SA
authors.lastname: Jensen
authors.forename: Henrik E
authors.initials: HE
authors.lastname: Poulsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D005472:Fluorouracil