title: Genotype-phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction.
abstract: 5-Fluorouracil is among the most widely used anticancer drug, but a fraction of treated patients develop severe toxicity, with potentially lethal injuries. The predictive power of the available pretreatment assays, used to identify patients at risk of severe toxicity, needs improvements. This study aimed to correlate a phenotypic marker of 5-fluorouracil metabolism (the individual degradation rate of 5-fluorouracil-5-FUDR) with 15 functional polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Single SNP (single-nucleotide polymorphism) analysis revealed that the SNPs rs1801160, rs1801265, rs2297595 and rs3918290 (splice site variant IVS14+1G>A) were significantly associated with a decreased value of 5-FUDR, and the rs3918290 causing the larger decrease. Multi-SNP analysis showed that a three-SNP haplotype (Hap7) involving rs1801160, rs1801265 and rs2297595 causes a marked decrease in 5-FUDR, comparable to that caused by the splice site variant rs3918290, which is the main pharmacogenetic marker associated with severe fluorouracil toxicity. The similar effect played by Hap7 and by the splice site variant rs3918290 upon individual 5-FUDR suggests that Hap7 could also represent a similar determinant of fluorouracil toxicity. Haplotype assessment could improve the predictive value of DPYD genetic markers aimed at the pre-emptive identification of patients at risk of severe 5-fluorouracil toxicity.The Pharmacogenomics Journal advance online publication, 28 July 2015; doi:10.1038/tpj.2015.56.
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.|Advanced Molecular Diagnostics Unit (DiMA), Sant'Andrea Hospital, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Oncology Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Botticelli
authors.affiliation: Advanced Molecular Diagnostics Unit (DiMA), Sant'Andrea Hospital, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: Oncology Unit, Sant'Andrea Hospital, Rome, Italy.|Department of Molecular and Clinical Medicine, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Mazzuca
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.|Advanced Molecular Diagnostics Unit (DiMA), Sant'Andrea Hospital, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: Oncology Unit, Sant'Andrea Hospital, Rome, Italy.|Department of Molecular and Clinical Medicine, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.|Advanced Molecular Diagnostics Unit (DiMA), Sant'Andrea Hospital, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Borro
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000378:metabolism*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008875:Middle Aged; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil