The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer

Shoaib Afzal, Milena Gusella, Søren Astrup Jensen, Ben Vainer, Ulla Vogel, Jon Thor Trærup Andersen, Kasper Brødbæk, Morten Petersen, Espen Victor Jimenez Solem, Vilmos Adleff, Barna Budau, Erika Hitre, Istvan Lang, Laura Bertolaso, Carmen Barile, Roberto Padrini, Judit Kralovanszky, Felice Pasini, Henrik Enghusen Poulsen

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    Abstract

    Aim: 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.
    Original languageEnglish
    JournalPharmacogenomics
    Volume12
    Issue number9
    Pages (from-to)1257-1267
    ISSN1462-2416
    DOIs
    Publication statusPublished - 2011

    Keywords

    • 5-fluorouracil
    • adjuvant chemotherapy
    • colorectal cancer
    • multifactor dimensionality
    • reduction method
    • pharmacogenetics

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