Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients

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, Ben

AU - Vogel, Ulla

AU - Andersen, Jon T

AU - Broedbaek, Kasper

AU - Petersen, Morten

AU - Jimenez-Solem, Espen

AU - Bertolaso, Laura

AU - Barile, Carmen

AU - Padrini, Roberto

AU - Pasini, Felice

AU - Jensen, Søren

AU - Poulsen, Henrik E

AU - Shoaib, Afzal

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Purpose: The purpose of this study was to investigate whether specific combinations of polymorphisms in genes encoding proteins involved in 5-fluorouracil (5-FU) 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 tetrahydrofolate reductase (MTHFR) were associated with decreased risk of toxicity [OR Exploration 0.39 (95% CI: 0.21-0.71, P = 0.003), OR Validation 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 (untranslated region) ins/del polymorphisms was significantly associated with increased toxicity in both cohorts [OR Exploration 2.40 (95% CI: 1.33-4.29, P = 0.003), OR Validation 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-FU treatment-related toxicity.

AB - Purpose: The purpose of this study was to investigate whether specific combinations of polymorphisms in genes encoding proteins involved in 5-fluorouracil (5-FU) 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 tetrahydrofolate reductase (MTHFR) were associated with decreased risk of toxicity [OR Exploration 0.39 (95% CI: 0.21-0.71, P = 0.003), OR Validation 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 (untranslated region) ins/del polymorphisms was significantly associated with increased toxicity in both cohorts [OR Exploration 2.40 (95% CI: 1.33-4.29, P = 0.003), OR Validation 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-FU treatment-related toxicity.

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

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

M3 - Journal article

C2 - 21471424

SN - 1078-0432

VL - 17

SP - 3822

JO - Clinical Cancer Research

JF - Clinical Cancer Research

ER -