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Integration of germline pharmacogenomic burden to predict fluoropyrimidine-related toxicity – A secondary analysis of the PREPARE trial

Oncogene volume 44, pages 4352–4362 (2025)Cite this article

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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.

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Fig. 1
Fig. 2: The landscape of genetic variants in the study population across all tested target genes.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the Italian Ministry of Health (Ricerca Corrente) and European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 668353. We also acknowledge funding from the Swedish Research Council [grant numbers: 2021-02801 and 2023-03015], by the SciLifeLab and Wallenberg National Program for Data-Driven Life Science [WASPDDLS22:006], Cancerfonden [23-0763PT and 24-3735Pj], the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2180—390900677, the Robert Bosch Foundation, Stuttgart, Germany, and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00209528).

Author information

Author notes

  1. These authors contributed equally: Elena De Mattia, Yoomi Park.

  2. These authors jointly supervised this work: Volker M. Lauschke, Erika Cecchin.

Authors and Affiliations

  1. Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081, Aviano, PN, Italy

    Elena De Mattia, Elena Peruzzi, Rossana Roncato, Lucia Scarabel, Giuseppe Toffoli & Erika Cecchin

  2. Department of Physiology and Pharmacology and Center for Molecular Medicine, Karolinska Institutet and University Hospital, 171 76, Stockholm, Sweden

    Yoomi Park, Yitian Zhou & Volker M. Lauschke

  3. Medical Research Center, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

    Yoomi Park

  4. Department of Medicine, University of Udine, via Colugna 50, 33100, Udine, Italy

    Rossana Roncato & Fabio Puglisi

  5. Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081, Aviano, PN, Italy

    Jerry Polesel

  6. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, 70376, Stuttgart, Germany

    Matthias Schwab & Volker M. Lauschke

  7. Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University Tuebingen, Geschwister-Scholl-Platz, 72074, Tübingen, Germania

    Matthias Schwab

  8. Cluster of excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University Tuebingen, Geschwister-Scholl-Platz, 72074, Tübingen, Germania

    Matthias Schwab

  9. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands

    Henk-Jan Guchelaar & Jesse Joachim Swen

  10. Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCSS, via Franco Gallini n. 2, 33081, Aviano, PN, Italy

    Michele Spina & Fabio Puglisi

  11. University of Tübingen, Geschwister-Scholl-Platz, 72074, Tübingen, Germany

    Volker M. Lauschke

  12. Department of Pharmacy, the Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan, 410011, China

    Volker M. Lauschke

Authors
  1. Elena De Mattia
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  2. Yoomi Park
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  3. Elena Peruzzi
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  4. Yitian Zhou
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  5. Rossana Roncato
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  6. Jerry Polesel
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  7. Lucia Scarabel
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  8. Matthias Schwab
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  9. Henk-Jan Guchelaar
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  10. Jesse Joachim Swen
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  11. Michele Spina
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  12. Fabio Puglisi
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  13. Giuseppe Toffoli
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  14. Volker M. Lauschke
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  15. Erika Cecchin
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Contributions

EDM, EC and VML conceptualized and designed the study. MS and FP provided and collected clinical samples and recorded clinical data. EDM directed and supervised the execution of sequencing experiments. EP, RR, and LS carried out sample processing and sequencing experiments. JP created the dataset by selecting matched cases and controls. YP and YZ carried out bio-informatic data processing and computational analysis. EDM, YP, VML and EC carried out interpretation of data. EDM and YP wrote the manuscript. EC, VML, GT, MS, HJG and JJS edited and revised the manuscript. EC and VML supervised the overall study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Volker M. Lauschke or Erika Cecchin.

Ethics declarations

Competing interests

VML is co-founder, CEO and shareholder of HepaPredict AB, as well as co-founder and shareholder of Shanghai Hepo Biotechnology Ltd. All other authors declare that they have no competing interests.

Ethics approval and consent to participate

The study population was selected from the prospective PREPARE trial (NCT03093818, ClinicalTrials.gov). The PREPARE study adhered to the principles outlined in the 1975 Declaration of Helsinki (with the 1983 revision) and was granted ethical approval by the local ethic committee. All patients provided written informed consent before entering the study to donate their anonymized blood samples for further studies including NGS analysis. All experiments were carried out in accordance with the relevant guidelines and regulations of Centro di Riferimento Oncologico di Aviano.

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De Mattia, E., Park, Y., Peruzzi, E. et al. Integration of germline pharmacogenomic burden to predict fluoropyrimidine-related toxicity – A secondary analysis of the PREPARE trial. Oncogene 44, 4352–4362 (2025). https://doi.org/10.1038/s41388-025-03587-7

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