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

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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.
    Original languageEnglish
    JournalClinical Cancer Research
    Volume17
    Issue number11
    Pages (from-to)3822-3829
    Number of pages9
    ISSN1078-0432
    DOIs
    Publication statusPublished - 2011

    Cite this

    Afzal, Shoaib ; Gusella, Milena ; Vainer, Bén ; Vogel, Ulla ; Andersen, Jon T. ; Broedbaek, Kasper ; Petersen, Morten ; Jiminez-solem, Espen ; Bertolaso, Laura ; Barile, Carmen ; Padrini, Roberto ; Pasini, Felice ; Jensen, Søren A. ; Enghusen Poulsen, Henrik. / Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy treated colorectal cancer patients. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 11. pp. 3822-3829.
    @article{05694512cbda432ca60d5856cff1825d,
    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 = "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.",
    author = "Shoaib Afzal and Milena Gusella and B{\'e}n Vainer and Ulla Vogel and Andersen, {Jon T.} and Kasper Broedbaek and Morten Petersen and Espen Jiminez-solem and Laura Bertolaso and Carmen Barile and Roberto Padrini and Felice Pasini and Jensen, {S{\o}ren A.} and {Enghusen Poulsen}, Henrik",
    year = "2011",
    doi = "10.1158/1078-0432.CCR-11-0304",
    language = "English",
    volume = "17",
    pages = "3822--3829",
    journal = "Clinical Cancer Research",
    issn = "1078-0432",
    publisher = "American Association for Cancer Research (A A C R)",
    number = "11",

    }

    Afzal, S, Gusella, M, Vainer, B, Vogel, U, Andersen, JT, Broedbaek, K, Petersen, M, Jiminez-solem, E, Bertolaso, L, Barile, C, Padrini, R, Pasini, F, Jensen, SA & Enghusen Poulsen, H 2011, 'Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy treated colorectal cancer patients', Clinical Cancer Research, vol. 17, no. 11, pp. 3822-3829. https://doi.org/10.1158/1078-0432.CCR-11-0304

    Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy treated colorectal cancer patients. / Afzal, Shoaib; Gusella, Milena; Vainer, Bén; Vogel, Ulla; Andersen, Jon T.; Broedbaek, Kasper; Petersen, Morten; Jiminez-solem, Espen; Bertolaso, Laura; Barile, Carmen; Padrini, Roberto; Pasini, Felice; Jensen, Søren A.; Enghusen Poulsen, Henrik.

    In: Clinical Cancer Research, Vol. 17, No. 11, 2011, p. 3822-3829.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy treated colorectal cancer patients

    AU - Afzal, Shoaib

    AU - Gusella, Milena

    AU - Vainer, Bén

    AU - Vogel, Ulla

    AU - Andersen, Jon T.

    AU - Broedbaek, Kasper

    AU - Petersen, Morten

    AU - Jiminez-solem, Espen

    AU - Bertolaso, Laura

    AU - Barile, Carmen

    AU - Padrini, Roberto

    AU - Pasini, Felice

    AU - Jensen, Søren A.

    AU - Enghusen Poulsen, Henrik

    PY - 2011

    Y1 - 2011

    N2 - 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.

    AB - 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.

    U2 - 10.1158/1078-0432.CCR-11-0304

    DO - 10.1158/1078-0432.CCR-11-0304

    M3 - Journal article

    VL - 17

    SP - 3822

    EP - 3829

    JO - Clinical Cancer Research

    JF - Clinical Cancer Research

    SN - 1078-0432

    IS - 11

    ER -