Vol.:(0123456789) 1 3 Cancer Chemotherapy and Pharmacology https://doi.org/10.1007/s00280-020-04093-1 ORIGINAL ARTICLE New DPYD variants causing DPD defciency in patients treated with fuoropyrimidine Xandra García‑González 1  · Bartosz Kaczmarczyk 1  · Judith Abarca‑Zabalía 1  · Fabienne Thomas 2  · Pilar García‑Alfonso 3  · Luis Robles 4  · Vanessa Pachón 5  · Ángeles Vaz 5  · Sara Salvador‑Martín 1  · María Sanjurjo‑Sáez 1  · Luis A. López‑Fernández 1 Received: 7 March 2020 / Accepted: 3 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Purpose Several clinical guidelines recommend genetic screening of DPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c.2846A>T, and c.1129-5923C>G, before initiating treatment with fuoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fuoropyrimidine- induced toxicity in patients. Methods Using a complementary approach combining whole DPYD exome sequencing and in silico and structural analysis, as well as phenotyping of DPD by measuring uracilemia (U), dihydrouracilemia (UH 2 ), and the UH 2 /U ratio in plasma, we were able to characterize and interpret DPYD variants in 28 patients with severe fuoropyrimidine-induced toxicity after negative screening. Results Twenty-fve out of 28 patients (90%) had at least 1 variant in the DPYD coding sequence, and 42% of the variants (6/14) were classifed as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifer. We identifed two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD defciency, as measured by the UH 2 /U ratio in a patient carrying the variant p.L775W for the frst time. Conclusion Whole exon sequencing of DPYD in patients with suspicion of partial DPD defciency can help to identify rare or new variants that lead to enzyme inactivation. Combining diferent techniques can yield abundant information without increasing workload and cost burden, thus making it a useful approach for implementation in patient care. Keywords Capecitabine · 5-Fluoruracil · Pharmacogenetics · Adverse reaction Abbreviations DPYD Dihydropyrimidine dehydrogenase gene DPD Dihydropyrimidine dehydrogenase protein 5-FU 5-Fluorouracil ADRs Adverse drug reactions CPIC Clinical Pharmacogenetics Implementation Consortium SNP Single-nucleotide polymorphism EMA European Medicines Agency Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04093-1) contains supplementary material, which is available to authorized users. * Luis A. López-Fernández luis.lopez@iisgm.com 1 Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain 2 Department of Pharmacology. Institut Claudius-Regaud. CRCT, Université de Toulouse. Inserm. UPS, 20-24 Rue du Pont Saint-Pierre, 31300 Toulouse, France 3 Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain 4 Medical Oncology Department, Hospital Universitario Doce de Octubre, Instituto de Investigación Hospital Doce de Octubre, Av. de Córdoba, s/n, 28041 Madrid, Spain 5 Medical Oncology Department, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), M-607, km. 9, 100, 28034 Madrid, Spain