Abstract
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. 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. 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. 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.
Highlights
5-Fluorouracil (5-FU) based adjuvant therapies for colorectal cancer reduce the risk of relapse and prolongs survival [1]
Purpose 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
A specific combination of the methylene tetrahyrofolate reductase (MTHFR) 1298A>C and thymidylate synthase (TYMS) 3’UTR ins/del polymorphisms was significantly associated with increased toxicity in both cohorts (ORExploration 2.40, ORValidation 1.81)
Summary
5-Fluorouracil (5-FU) based adjuvant therapies for colorectal cancer reduce the risk of relapse and prolongs survival [1]. Systemic toxicity is increased by constitutive factors that decrease 5-FU elimination or increase 5-FU activity in non-tumor tissues. This is evidenced by several studies showing that factors influencing 5-FU clearance, such as sex, age and dihydropyrimidine dehydrogenase (DPYD) activity, influence the risk of toxicity [2,3,4]. The results have been contradictory, probably due to treatment differences, different patient populations, inadequate statistical analyses and chance findings Most of these studies investigate the association of individual polymorphisms with severe toxicity, while the associations of haplotypes [7] and genetic interactions with 5-FU toxicity have largely been overlooked, partly due to lack of reliable methods to study genetic interactio
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