Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy treated colorectal cancer patients

Shoaib Afzal, Milena Gusella, Bén Vainer, Ulla Vogel, Jon T. Andersen, Kasper Broedbaek, Morten Petersen, Espen Jiminez-solem, Laura Bertolaso, Carmen Barile, Roberto Padrini, Felice Pasini, Søren A. Jensen, Henrik Enghusen Poulsen

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    Purpose: The purpose of this study was to investigate whether specific combinations of polymorphisms in genes encoding proteins involved in 5-Fluorouracil pharmacokinetics and pharmacodynamics are associated with increased risk of treatment-induced toxicity.

    Experimental Design: 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 tetrahyrofolate reductase (MTHFR) were associated with decreased risk of toxicity (ORExploration 0.39 (95 % CI: 0.21 - 0.71, p = 0.003), ORValidation 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 ins/del polymorphisms was significantly associated with increased toxicity in both cohorts (ORExploration 2.40 (95 % CI: 1.33 - 4.29, p = 0.003), ORValidation 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-Fluorouracil treatment related toxicity.
    TidsskriftClinical Cancer Research
    Udgave nummer11
    Sider (fra-til)3822-3829
    Antal sider9
    StatusUdgivet - 2011

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