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

TY - JOUR

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

AU - Shoaib, Afzal

AU - Gusella, Milena

AU - Jensen, Søren Astrup

AU - Vainer, Ben

AU - Vogel, Ulla Birgitte

AU - Andersen, Jon Trærup

AU - Brødbæk, Kasper

AU - Petersen, Morten

AU - Jimenez-Solem, Espen

AU - Adleff, Vilmos

AU - Budai, Barna

AU - Hitre, Erika

AU - Láng, István

AU - Orosz, Eniko

AU - Bertolaso, Laura

AU - Barile, Carmen

AU - Padrini, Roberto

AU - Kralovánszky, Judit

AU - Pasini, Felice

AU - Poulsen, Henrik Enghusen

PY - 2011/9

Y1 - 2011/9

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. Original submitted 13 April 2011; Revision submitted 10 June 201.

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. Original submitted 13 April 2011; Revision submitted 10 June 201.

U2 - 10.2217/pgs.11.83

DO - 10.2217/pgs.11.83

M3 - Journal article

C2 - 21919605

SN - 1462-2416

VL - 12

SP - 1257

EP - 1267

JO - Pharmacogenomics

JF - Pharmacogenomics

IS - 9

ER -