Genotype-Phenotype Predictive Gap in Pre-Emptive Screening of DPD Deficiency: Improving Sensitivity.
- 1Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
- 2Laboratory of Clinical Biochemistry and Molecular Biology, Sant'Andrea Hospital of Rome, 00189 Rome, Italy.
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.
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BibTeX
@article{salerno2026genotypephenotype,
title = {{Genotype-Phenotype Predictive Gap in Pre-Emptive Screening of DPD Deficiency: Improving Sensitivity.}},
author = {Gerardo Salerno and Ottavia De Luca and Caterina Ilari and Maurizio Simmaco and Marina Borro},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/ph19101551},
url = {https://europepmc.org/article/MED/42943248},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genotype-Phenotype Predictive Gap in Pre-Emptive Screening of DPD Deficiency: Improving Sensitivity.
AU - Gerardo Salerno
AU - Ottavia De Luca
AU - Caterina Ilari
AU - Maurizio Simmaco
AU - Marina Borro
PY - 2026
DA - 2026/09/30
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101551
UR - https://europepmc.org/article/MED/42943248
AB - 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.
SN - 1424-8247
ER -