Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity: Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays.

Content Provider	Europe PMC
Author	De Luca, Ottavia Salerno, Gerardo De Bernardini, Donatella Torre, Maria Simona Simmaco, Maurizio Lionetto, Luana Gentile, Giovanna Borro, Marina
Editor	Cacabelos, Ramón
Copyright Year	2022
Abstract	Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype−phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype−phenotype association data is needed to enable the clinical use of sequencing data.
Journal	International Journal of Molecular Sciences [Int J Mol Sci]
Volume Number	23
DOI	10.3390/ijms232213923
PubMed Central reference number	PMC9694733
Issue Number	22
PubMed reference number	36430399
e-ISSN	14220067
Language	English
Publisher	Molecular Diversity Preservation International (MDPI)
Publisher Date	2022-11-11
Access Restriction	Open
Subject Keyword	5-fluorouracil DPYD dihydropyrimidine dehydrogenase next generation sequencing polymorphism phenotyping genotyping
Content Type	Text
Resource Type	Article
Subject	Physical and Theoretical Chemistry Molecular Biology Spectroscopy Catalysis Computer Science Applications Medicine Inorganic Chemistry Organic Chemistry