Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients
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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, Ben; Vogel, Ulla; Andersen, Jon T; Broedbaek, Kasper; Petersen, Morten; Jimenez-Solem, Espen; Bertolaso, Laura; Barile, Carmen; Padrini, Roberto; Pasini, Felice; Jensen, Søren; Poulsen, Henrik E.
In: Clinical Cancer Research, Vol. 17, 17.05.2011, p. 3822.Research output: Contribution to journal › Journal article › Research › peer-review
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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
PY - 2011/5/17
Y1 - 2011/5/17
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. Clin Cancer Res; 17(11); 1-8. ©2011 AACR.
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. Clin Cancer Res; 17(11); 1-8. ©2011 AACR.
U2 - 10.1158/1078-0432.CCR-11-0304
DO - 10.1158/1078-0432.CCR-11-0304
M3 - Journal article
C2 - 21471424
VL - 17
SP - 3822
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
ER -
ID: 34052802