Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity

Abstract

Background: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.

Methods: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.

Results: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻⁶, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively).

Conclusion: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

Figure 1

Capecitabine and 5-FU metabolism. Enzymes: Carboxyl esterase (CES), deoxycytidine kinase (dCK), deoxycytidine monophosphate deaminase (dCMDA), cytidine deaminase (CDA), thymidine phosphorylase (TP), uridine phosphorylase (UP), dihydropyrimidine dehydrogenase (DPYD), dihydropyrimidinase (DPYS), orotate phosphoribosyltransferase (OPRT), uridine kinase (UK), uridine monophosphate kinase (UMPK), uridine diphosphate kinase (UDPK), ribonucleotide reductase (RNR), thymidine kinase (TK), thymidine synthase (TS), deoxyuridine triphosphatase (DUT), methylene tetrahydrofolate reductase (MTHFR). Metabolites: deoxyfluorocytidine riboside (5′-dFCR), deoxyfluorocytidine monophosphate (5′-dFCMP), deoxyfluorouridine monophosphate (5-FdUMP), deoxyfluorouracil (5′-dFUR), fluorouracil (5-FU), fluorouridine (5-FUridine), fluorouracil monophosphate (5-FUMP), fluorouracil di, tri-phosphate (5-FUDP, 5-FUTP), deoxyfluorouracil di, tri-phosphate (5-FdUDP, 5-FdUTP), deoxyuridine mono, tri –phosphate (dUMP, dUTP), deoxycytidine mono, tri-phosphate (dTMP, dTTP), 5,10-methylenetetrahydrofolate (5,10-MTHF), 5-methyltetrahydrofolate (5-MeTHF), dihydrofolate (DHF), dihydrofluorouracil (DHFU), beta-fluoroureido propionic acid (β-FUPA).

Figure 2

Receiver-operating characteristic curves for the prediction models with all variables (rare DPYD variants, common variants, clinical variables) for all patients (A) and the capecitabine cohort (B).