New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine.

Cancer Chemotherapy and Pharmacology
Xandra García-GonzálezLuis A López-Fernández

Abstract

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 fluoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fluoropyrimidine-induced toxicity in patients. 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 (UH2), and the UH2/U ratio in plasma, we were able to characterize and interpret DPYD variants in 28 patients with severe fluoropyrimidine-induced toxicity after negative screening. Twenty-five out of 28 patients (90%) had at least 1 variant in the DPYD coding sequence, and 42% of the variants (6/14) were classified as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifier. We identified two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD deficiency, as measured by the UH2/U ratio in a patient carrying the variant p.L775W for the first time. Whole exon sequencing of DPYD ...Continue Reading

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Oct 24, 2018·Cancer Management and Research·Xandra García-GonzálezLuis Andrés López-Fernández

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Citations

Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maureen Bilinga TendwaÖzlem Tastan Bishop
Aug 28, 2021·Journal of Personalized Medicine·Priscila VillalvazoLuis Andrés López-Fernández
Nov 14, 2021·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·P García-AlfonsoF Abad-Santos

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