Genotype-Phenotype Predictive Gap in Pre-Emptive Screening of DPD Deficiency: Improving Sensitivity.

Authors

Gerardo Salerno, Ottavia De Luca, Caterina Ilari, Maurizio Simmaco, Marina Borro

Published in

Pharmaceuticals (Basel, Switzerland). Volume 19. Issue 10. Sep 30, 2026. Epub Sep 30, 2026.

Abstract

Background/Objectives: toxicity related to treatment with the anti-cancer drugs fluoropyrimidines (FP) is mainly driven by a deficiency in the dihydropyrimidine-dehydrogenase (DPD) enzyme activity. Standardized pharmacogenomic markers in the DPYD gene allow pre-emptive prediction and therapy adjustment in patients testing positive, but the rarity of these markers lowers screening sensitivity, leaving a significant part of at-risk individuals undetected. This study aimed to explore the diagnostic performance of genetic screening tests modelled to include unclassified rare DPYD variants and the common SNPs rs1801160 and rs2297595. Methods: this is a retrospective genotype-phenotype association study including 687 Italian subjects who underwent DPD-phenotyping by the 5-fluorouracil degradation assay (5-FUDR) and DPYD genotyping by full exon sequencing. According to their DPD-phenotype, subjects were grouped into a DPD deficiency group (DD, N = 94; >30% reduction in 5-FUDR) and a normal DPD activity group (NDA, N = 593). The phenotype was used as the reference standard to assess genotype-based functional prediction, and discordant genotype-phenotype cases were scored as false negatives or false positives. The phenotype (DD or NDA) prediction power of a genetic, binary (presence/absence) screening test including standardized pharmacogenomic markers (Test 1) was compared to binary tests including missense, nonsense, frameshift or splice-site rare variants (Test 2) or the co-occurrence of rs1801160 and rs2297595 (Test 3). Statistical significance was set at p < 0.05, correcting for multiple testing when appropriate. Results: positivity for all binary tests was significantly associated with the DPD deficiency phenotype (Test1: OR = 6; Test 2: OR = 4.85; Test3: OR = 4.9). Notably, overlap among subjects testing positive in the different tests was minimal. Combining all tests, a 3-fold increase in screening sensitivity was achieved compared to the reference Test 1 (from 12.77% to 35.11%), with a slight decrease in specificity from 97.64% to 91.74%. Conclusions: the proposed approach can refine the genetic predictivity of the DPD-deficiency phenotype in pre-emptive screening, capturing a significantly larger pool of biochemically at-risk patients.

PMID:
42943248
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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