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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Resumé

    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.
    OriginalsprogEngelsk
    TidsskriftPharmacogenomics
    Vol/bind12
    Udgave nummer9
    Sider (fra-til)1257-1267
    ISSN1462-2416
    DOI
    StatusUdgivet - 2011

    Citer dette

    Afzal, S., Gusella, M., Jensen, S. A., Vainer, B., Vogel, U., Andersen, J. T. T., ... Poulsen, H. E. (2011). The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. Pharmacogenomics, 12(9), 1257-1267. https://doi.org/10.2217/pgs.11.83
    Afzal, Shoaib ; Gusella, Milena ; Jensen, Søren Astrup ; Vainer, Ben ; Vogel, Ulla ; Andersen, Jon Thor Trærup ; Brødbæk, Kasper ; Petersen, Morten ; Solem, Espen Victor Jimenez ; Adleff, Vilmos ; Budau, Barna ; Hitre, Erika ; Lang, Istvan ; Bertolaso, Laura ; Barile, Carmen ; Padrini, Roberto ; Kralovanszky, Judit ; Pasini, Felice ; Poulsen, Henrik Enghusen. / The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. I: Pharmacogenomics. 2011 ; Bind 12, Nr. 9. s. 1257-1267.
    @article{cf60d15e60414c5f9852d5de02ee83ab,
    title = "The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer",
    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.",
    keywords = "5-fluorouracil, adjuvant chemotherapy, colorectal cancer, multifactor dimensionality , reduction method, pharmacogenetics",
    author = "Shoaib Afzal and Milena Gusella and Jensen, {S{\o}ren Astrup} and Ben Vainer and Ulla Vogel and Andersen, {Jon Thor Tr{\ae}rup} and Kasper Br{\o}db{\ae}k and Morten Petersen and Solem, {Espen Victor Jimenez} and Vilmos Adleff and Barna Budau and Erika Hitre and Istvan Lang and Laura Bertolaso and Carmen Barile and Roberto Padrini and Judit Kralovanszky and Felice Pasini and Poulsen, {Henrik Enghusen}",
    year = "2011",
    doi = "10.2217/pgs.11.83",
    language = "English",
    volume = "12",
    pages = "1257--1267",
    journal = "Pharmacogenomics",
    issn = "1462-2416",
    publisher = "Future Medicine Ltd.",
    number = "9",

    }

    Afzal, S, Gusella, M, Jensen, SA, Vainer, B, Vogel, U, Andersen, JTT, Brødbæk, K, Petersen, M, Solem, EVJ, Adleff, V, Budau, B, Hitre, E, Lang, I, Bertolaso, L, Barile, C, Padrini, R, Kralovanszky, J, Pasini, F & Poulsen, HE 2011, 'The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer', Pharmacogenomics, bind 12, nr. 9, s. 1257-1267. https://doi.org/10.2217/pgs.11.83

    The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. / Afzal, Shoaib; Gusella, Milena; Jensen, Søren Astrup; Vainer, Ben; Vogel, Ulla; Andersen, Jon Thor Trærup; Brødbæk, Kasper; Petersen, Morten; Solem, Espen Victor Jimenez; Adleff, Vilmos; Budau, Barna; Hitre, Erika; Lang, Istvan; Bertolaso, Laura; Barile, Carmen; Padrini, Roberto; Kralovanszky, Judit; Pasini, Felice; Poulsen, Henrik Enghusen.

    I: Pharmacogenomics, Bind 12, Nr. 9, 2011, s. 1257-1267.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer

    AU - Afzal, Shoaib

    AU - Gusella, Milena

    AU - Jensen, Søren Astrup

    AU - Vainer, Ben

    AU - Vogel, Ulla

    AU - Andersen, Jon Thor Trærup

    AU - Brødbæk, Kasper

    AU - Petersen, Morten

    AU - Solem, Espen Victor Jimenez

    AU - Adleff, Vilmos

    AU - Budau, Barna

    AU - Hitre, Erika

    AU - Lang, Istvan

    AU - Bertolaso, Laura

    AU - Barile, Carmen

    AU - Padrini, Roberto

    AU - Kralovanszky, Judit

    AU - Pasini, Felice

    AU - Poulsen, Henrik Enghusen

    PY - 2011

    Y1 - 2011

    N2 - 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.

    AB - 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.

    KW - 5-fluorouracil

    KW - adjuvant chemotherapy

    KW - colorectal cancer

    KW - multifactor dimensionality

    KW - reduction method

    KW - pharmacogenetics

    U2 - 10.2217/pgs.11.83

    DO - 10.2217/pgs.11.83

    M3 - Journal article

    VL - 12

    SP - 1257

    EP - 1267

    JO - Pharmacogenomics

    JF - Pharmacogenomics

    SN - 1462-2416

    IS - 9

    ER -