title: Uncommon dihydropyrimidine dehydrogenase mutations and toxicity by fluoropyrimidines: a lethal case with a new variant.
abstract: DPD is the rate-limiting enzyme involved in the metabolism of 5-fluorouracil and its prodrugs, capecitabine and tegafur. Many cases of severe toxicities by fluoropyrimidines are reported in the literature, sometimes with lethal outcome, due to a poor or null metabolizer phenotype. The exon 14-skipping mutation IVS14+1G>A and the c.2846A>T are the most common deficient variants. However, many additional variants of the DPYD gene with unclear functional significance have been reported. We describe a patient with metastatic breast cancer who received capecitabine and trastuzumab at standard doses. Six days after beginning capecitabine, the patient developed fever, leucopenia and neutropenia, mucositis, hand-foot syndrome, multiple organ dysfunction and eventually died. Since the toxicity profile was compatible with capecitabine administration, complete exon sequencing of DPYD was carried out and the patient was found to be compound heterozygous for the rare mutation c.257C>T in exon 4, c.496A>G in exon 6, the new variant c.1850C>T in exon 14 and c.2194G>A in exon 18. Given the marginal role of c.496A>G and c.2194G>A in DPD deficiency, the cause of death was suggested to be dependent on the novel c.1850C>T in combination with c.257C>T. The complexity of DPD pharmacogenetics suggests the need to develop cost-effective screening approaches to identify patients at risk of severe toxicities.
authors.affiliation: Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, 55, Via Roma, I-56126 Pisa, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Del Re
authors.affiliation: Departmental Unit of Medical Oncology, IRCCS Fondazione Maugeri, 4, Via Salvatore Maugeri, I-27100 Pavia, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Quaquarini
authors.affiliation: Departmental Unit of Medical Oncology, IRCCS Fondazione Maugeri, 4, Via Salvatore Maugeri, I-27100 Pavia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Sottotetti
authors.affiliation: Unit of Medical Genetics, Department of Laboratory Medicine, University Hospital, 67, Via Roma, I-56126 Pisa, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Michelucci
authors.affiliation: Departmental Unit of Medical Oncology, IRCCS Fondazione Maugeri, 4, Via Salvatore Maugeri, I-27100 Pavia, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Palumbo
authors.affiliation: Unit of Medical Genetics, Department of Laboratory Medicine, University Hospital, 67, Via Roma, I-56126 Pisa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Simi
authors.affiliation: Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, 55, Via Roma, I-56126 Pisa, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Departmental Unit of Medical Oncology, IRCCS Fondazione Maugeri, 4, Via Salvatore Maugeri, I-27100 Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernardo
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine / Q000008:administration & dosage; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000556:secondary; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D009154:Mutation; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D000068878:Trastuzumab
keywords: 5-FU; DPYD; capecitabine; pharmacogenetics; toxicity