Background: The variant rs34983651 (UGT1A1*28) and its genotyping are used to prevent irinotecan-induced toxicity. Several variants are in close linkage disequilibrium. Our objective was to evaluate the potential correlation of genotyping UGT1A1*80 instead of UGT1A1*28 in different populations. Methods: We studied SNPs in linkage disequilibrium with UGT1A1*28 in several populations and selected rs887829 to develop an inexpensive and rapid genotyping method and compare it with the one we currently use for UGT1A1*28 genotyping. Samples from cancer patients (n = 701) already tested using PCR and electrophoresis prior to treatment with irinotecan for rs34983651 (UGT1A1*28) in a Spanish hospital were genotyped for rs887829 (UGT1A1*80) using real-time PCR with a TaqMan probe. Results: We observed a complete match for both genotypes, except in one sample. This method was 100% efficient in correctly genotyping *28/*28 patients, 99.68% efficient for *1/*28, and 100% efficient for *1/*1. Linkage disequilibrium between populations showed the Iberian population to be the most suitable for the clinical use of UGT1A1*80. This method is less expensive and the time to decision is shorter. Conclusion: Genotyping of rs887829 using the proposed method may be used to substitute genotyping of rs34983651 as a pharmacogenetics test in cancer patients prior to starting irinotecan-based treatments, mainly in the Iberian population. In addition, it is less expensive than other conventional methods and easy to implement, with a shorter time to decision than UGT1A1*28.

Background/Objectives: As a treatment, fluoropyrimidines are often associated with early moderate-to-severe toxicity. Although pre-emptive DPYD genotyping enables genotype-guided dosing, significant adverse events still occur in patients classified as DPYD wild-type (WT). The aim of this study was to identify DPYD variants and evaluate the contributions of TYMS, ENOSF1, CDH4, and CDA variants to fluoropyrimidine toxicity. Methods: A total of 256 European ancestry patients (aged ≥ 18 years, had completed ≥6 cycles of chemotherapy, and were WT for the DPYD variants routinely tested for) underwent genotyping for TYMS, ENOSF1, CDH4, and CDA variants, and full DPYD exon sequencing was performed in 56 of these patients. Toxicity was defined as fluoropyrimidine-related adverse events requiring a dose reduction. Multivariable models were adjusted for sex, fluoropyrimidine type, and the Charlson Comorbidity Index, and time-to-event was assessed using the Kaplan–Meier/Cox proportional hazards models. Results: A subgroup of 117 patients experienced toxicity requiring a dose reduction. The most frequent events were asthenia, gastrointestinal toxicity, hand–foot syndrome, and haematological toxicity. The ENOSF1 rs2612091 C allele was associated with fluoropyrimidine withdrawal and a shorter time to dose reduction. In the patients treated with 5-fluorouracil, TYMS rs11280056 was associated with toxicity. DPYD exon sequencing identified thirteen variants, nine of which were more prevalent in the toxicity group. These included a canonical splice site (c.150+1G>A) and a stop-gained (c.1863G>A) variant, which is predicted to result in loss of function. Conclusions: In real-world practice, despite undergoing standard DPYD genotyping, DPYD WT patients receiving a full dose of fluoropyrimidines develop clinically relevant toxicity. The presence of rare DPYD variants and associated genes (ENOSF1 and TYMS) suggests that broader, prospectively validated pharmacogenetic strategies may improve toxicity prevention.