title: Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase.
abstract: Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%-30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients' homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies' results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan 20157, Italy. falvella.stefania@hsacco.it.
authors.forename: Felicia Stefania
authors.initials: FS
authors.lastname: Falvella
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. marta.caporale@istitutotumori.mi.it.
authors.forename: Marta
authors.initials: M
authors.lastname: Caporale
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan 20157, Italy. cheli.stefania@hsacco.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cheli
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. antonia.martinetti@istitutotumori.mi.it.
authors.forename: Antonia
authors.initials: A
authors.lastname: Martinetti
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. rosa.berenato@istitutotumori.mi.it.
authors.forename: Rosa
authors.initials: R
authors.lastname: Berenato
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. claudia.maggi@istitutotumori.mi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maggi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. monica.niger@istitutotumori.mi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Niger
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. francesca.ricchini@istitutotumori.mi.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricchini
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. ilaria.bossi@istitutotumori.mi.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bossi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. maria.dibartolomeo@istitutotumori.mi.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Di Bartolomeo
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. elisa.sottotetti@istitutotumori.mi.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Sottotetti
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", Faculty of Medicine and Surgery, Second University of Naples, Naples 80138, Italy. bernardi.francesca.futura@gmail.com.
authors.forename: Francesca Futura
authors.initials: FF
authors.lastname: Bernardi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. filippo.debraud@istitutotumori.mi.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco 23842, Italy. emilio.clementi@unimi.it.|Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital "Luigi Sacco", Università di Milano, Milan 20157, Italy. emilio.clementi@unimi.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, Milan 20133, Italy. filippo.pietrantonio@istitutotumori.mi.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pietrantonio
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D044127:Epigenesis, Genetic; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D005787:Gene Frequency; D006801:Humans; D020641:Polymorphism, Single Nucleotide
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil