Identification of a large DPYD gene deletion undetected by standard genotyping in a patient with severe capecitabine-related toxicity: a case report

Background Fluoropyrimidines are widely used in the treatment of multiple neoplasms, but their use is limited by the risk of severe toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. Current clinical guidelines recommend DPYD genotyping as pre-treatment screening for a limited number of common variants; however, this approach fails to identify all patients at risk. Case Description We describe the case of a man with resected gastric adenocarcinoma, wild type for the DPYD recommended variants, who developed early-onset, life-threatening toxicity shortly after few days of adjuvant capecitabine-based chemotherapy at full dose. The clinical course was characterized by grade 4 gastrointestinal toxicity complicated by septic shock, which required prolonged hospitalization and led to the definitive discontinuation of chemotherapy. Extensive Next-Generation Sequencing (NGS) revealed a heterozygous deletion spanning from exons 5 to 20 (for a total of about 500 Kb) of the DPYD gene. The presence of this deletion was validated using Single Nucleotide Polymorphism (SNP) Array. Functional analysis, based on assessment of DPD activity in peripheral blood mononuclear cells (PBMCs) and plasma concentrations of uracil and dihydrouracil, confirmed the impaired DPD function. Conclusion This case highlights the limitations of routine DPYD genotyping strategies and emphasizes the clinical relevance of rare structural variants as an underestimated cause of severe fluoropyrimidine-related toxicity. The use of comprehensive NGS approach in pharmacogenetic diagnostics should be considered as a step forward in the identification of patients at risk of fluoropyrimidines-related toxicity particularly in the context of adjuvant therapy, where it is essential to strike a balance between therapeutic benefits and unacceptable toxicity.