Variants in the Dihydropyrimidine Dehydrogenase, Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes Predict Early Toxicity of 5-Fluorouracil in Colorectal Cancer Patients

Abstract

Adverse drug reactions to 5-fluorouracil (5-FU)-based chemotherapy have been reported to be due, in part, to genetic variants of the genes for the drug-related enzymes thymidylate synthase (TS; TYMS gene), methylenetetrahydrofolate reductase (MTHFR gene) and dihydropyrimidine dehydrogenase (DPD; DPYD gene). This study investigated whether selected genetic variants of the TYMS, MTHFR and DPYD genes predict 5-FU-related early toxicity. The prevalence of the genetic variants was determined in 122 colorectal cancer patients and in a reference population of 320 blood donors. Subgroup analysis of 68 of the colorectal cancer patients was carried out to determine the relationship between selected gene variants detected in peripheral mononuclear cells and tolerability during the first or second cycle of 5-FU based treatment. Toxicity was linked to the TYMS 2R/2R variant (relative risk [RR] 1.66; sensitivity 0.37; specificity 0.77) and to the MTHFR c1298 C/C genetic variant (RR 1.77; sensitivity 0.17; specificity 0.91). Patients with the genetic variant IVS14+1 G/A or c1896 C/T in the DPYD gene had a statistically significant increased risk of experiencing toxicity (RR 2 and 6, respectively), both having a high specificity (0.97 and 0.98, respectively) and low sensitivity (0.04 and 0.13, respectively). It is concluded that pre-treatment detection of genetic variants can help to predict early toxicity experienced by patients receiving 5-FU-based chemotherapy.