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Updated: Jan 16, 2026
Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer
Published on: May 10, 2024
Integration of germline pharmacogenomic burden to predict fluoropyrimidine-related toxicity - A secondary analysis of
Elena De Mattia1, Yoomi Park2,3, Elena Peruzzi1
1Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081, Aviano, PN, Italy.
Abstract:
Testing for four dihydropyrimidine dehydrogenase (DPYD) variants (DPYD*2 A, DPYD*13, c.2846 A > T, DPYD-HapB3) is currently implemented in clinical practice to prevent fluoropyrimidines (FLs) related toxicity but with limited sensitivity. This study aimed to identify novel genetic factors in FL-related genes to enhance risk prediction using data from the PREPARE trial (NCT03093818). Two hundred seventy-four patients receiving FL-based chemotherapy with severe toxicity were sequenced for 60 candidate genes. Gene and pathway-level association analyses focusing mainly on rare variants were performed using dedicated statistical tests, including gene-wise variant burden (GVB) analysis. DPYD germline variant burden beyond the four routinely tested markers emerged to contribute to toxicity, indicating that rarer genetic variants could help in refining the optimal FL dosage (p < 0.1). Functional rare variant burden in ABCB5, PARP1, ENOSF1, CYP3A4 and nuclear receptors pathway impacted on toxicity risk (p < 0.05 in at least one statistical test). GVB analysis confirmed ABCB5 as a significant risk gene and highlighted ABCC4, HNF4A, and XRCC3 as additional candidates. A predictive model combining genetic burden scores with clinical variables improved the identification of high-risk patients (sensitivity=0.71, specificity=0.74, accuracy=0.73). This study indicated a paradigm shift from population to individual-level arguing for an extension of testing beyond the four DPYD currently considered variants to predict FL-related toxicity.
Insights
Identifying rare genetic variants beyond the four standard DPYD markers improves prediction of fluoropyrimidine toxicity. This expands genetic testing for personalized chemotherapy dosing and reduced adverse events.
Area of Science:
- Pharmacogenomics
- Oncology
- Genetics
Background:
- Current dihydropyrimidine dehydrogenase (DPYD) variant testing has limited sensitivity for predicting fluoropyrimidine (FL) toxicity.
- Personalized medicine approaches are needed to optimize FL dosage and minimize severe adverse events.
Purpose of the Study:
- To identify novel genetic factors, including rare variants, associated with FL-related toxicity.
- To enhance risk prediction models for FL chemotherapy.
Main Methods:
- Whole-exome sequencing of 60 candidate genes in 274 patients with severe FL toxicity.
- Gene-wise variant burden (GVB) and pathway-level association analyses focusing on rare variants.
- Development of a predictive model integrating genetic burden scores and clinical variables.
Main Results:
- DPYD germline variant burden beyond the four routinely tested markers contributes to toxicity.
- Rare variant burden in ABCB5, PARP1, ENOSF1, CYP3A4, and the nuclear receptors pathway impacted toxicity risk.
- A predictive model combining genetic and clinical factors achieved 73% accuracy in identifying high-risk patients.
Conclusions:
- Extending genetic testing beyond the four common DPYD variants is crucial for accurate FL toxicity prediction.
- Rare genetic variants play a significant role in individualizing FL dosage and improving patient outcomes.
- A paradigm shift towards individual-level genetic assessment is necessary for safer chemotherapy.
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