{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:09:21Z","timestamp":1792786161595,"version":"4.5.0"},"reference-count":11,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","funder":[{"name":"Rambam Health Care campus intra mural grant","award":["1-820"],"award-info":[{"award-number":["1-820"]}],"id":[{"id":"https:\/\/ror.org\/01fm87m50","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,11]]},"abstract":"\n \n \n Pre-emptive genotyping and genotype-guided dose adjustments are generally recommended for seven hypofunctional polymorphisms in the\n DPYD<\/jats:italic>\n gene that are associated with fluoropyrimidine toxicity. However, targeted genotyping may miss uncommon and population-specific hypofunctional variants. Therefore, in 2021, we replaced conventional targeted genotyping with comprehensive\n DPYD<\/jats:italic>\n exome sequencing. The objective of the current study was to identify uncommon hypofunctional variants and assess their association with fluoropyrimidine toxicity. In a cohort of 762 consecutive patients pre-emptively genotyped between 2021 and 2025, among the seven established risk variants, we identified *2A and HapB3 at their expected minor allele frequencies (MAF), but no carriers of any of the five other established risk variants. Interestingly, four patients were heterozygous for the rare missense c.257C>T variant (Pro86Leu; rs568132506), previously associated with fluoropyrimidine toxicity. The MAF (2.62\u2005\u00d7\u200510\n \u22123<\/jats:sup>\n ) was similar to that previously described in Middle Eastern populations but 26-fold higher than in the gnomAD global population. Three of the carriers (75%) developed grade 3\u20134 fluoropyrimidine toxicity after one or two cycles, corresponding to a relative risk of 14.5 (95% confidence interval: 5.0\u201330.4,\n P<\/jats:italic>\n \u2005=\u20050.0009) compared with a control cohort without hypofunctional\n DPYD<\/jats:italic>\n variants. Our findings add to the growing body of evidence indicating that\n DPYD<\/jats:italic>\n c.257C>T may be associated with severe fluoropyrimidine toxicity. Future studies should examine the clinical utility of including uncommon but potentially actionable variants, such as c.257C>T, into pre-emptive genotyping algorithms. This may be particularly important in multiethnic populations in which these variants can be more prevalent than those variants for which pre-emptive genotyping is generally recommended.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000616","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T16:00:07Z","timestamp":1788105607000},"page":"290-294","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Prevalence and clinical impact of the uncommon DPYD c.257C>T (Pro86Leu) variant in a multiethnic cohort receiving fluoropyrimidine therapy"],"prefix":"10.1097","volume":"36","author":[{"given":"Marie-Jeanne","family":"Carp","sequence":"first","affiliation":[{"name":"Section of Clinical Pharmacology and Toxicology, Rambam Health Care Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Ring","sequence":"additional","affiliation":[{"name":"Section of Clinical Pharmacology and Toxicology, Rambam Health Care Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ithai","family":"Waldhorn","sequence":"additional","affiliation":[{"name":"Division of Oncology, Rambam Health Care Campus"},{"name":"Rappaport Faculty of Medicine, Technion \u2013 Israel Institute of Technology, Haifa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Shempliner","sequence":"additional","affiliation":[{"name":"Section of Clinical Pharmacology and Toxicology, Rambam Health Care Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Schantzer","sequence":"additional","affiliation":[{"name":"Division of Oncology, Rambam Health Care Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa","family":"Mor","sequence":"additional","affiliation":[{"name":"Samson Assuta Ashdod University Hospital, Ashdod"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Ryvo","sequence":"additional","affiliation":[{"name":"Samson Assuta Ashdod University Hospital, Ashdod"},{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kurnik","sequence":"additional","affiliation":[{"name":"Section of Clinical Pharmacology and Toxicology, Rambam Health Care Campus"},{"name":"Rappaport Faculty of Medicine, Technion \u2013 Israel Institute of Technology, Haifa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edna","family":"Efrati","sequence":"additional","affiliation":[{"name":"Section of Clinical Pharmacology and Toxicology, Rambam Health Care Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"R1-20261002","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/cpt.911","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update.","volume":"103","author":"Amstutz","year":"2018","journal-title":"Clin Pharmacol Ther"},{"key":"R2-20261002","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.jmoldx.2024.05.015","article-title":"DPYD genotyping recommendations: a Joint Consensus Recommendation of the Association for Molecular Pathology, American College of Medical Genetics and Genomics, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy.","volume":"26","author":"Pratt","year":"2024","journal-title":"J Mol Diagn"},{"key":"R3-20261002","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1038\/bjc.2017.94","article-title":"Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity.","volume":"116","author":"Meulendijks","year":"2017","journal-title":"Br J Cancer"},{"key":"R4-20261002","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1002\/cpt.531","article-title":"Novel deleterious dihydropyrimidine dehydrogenase variants may contribute to 5-fluorouracil sensitivity in an East African population.","volume":"101","author":"Elraiyah","year":"2017","journal-title":"Clin Pharmacol Ther"},{"key":"R5-20261002","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1042\/bj3640157","article-title":"Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure.","volume":"364","author":"van Kuilenburg","year":"2002","journal-title":"Biochem J"},{"key":"R6-20261002","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3390\/clinpract11030062","article-title":"Fluoropyrimidine-induced severe toxicities associated with rare DPYD polymorphisms: case series from Saudi Arabia and a review of the literature.","volume":"11","author":"Bukhari","year":"2021","journal-title":"Clin Pract"},{"key":"R7-20261002","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.bbadis.2016.12.010","article-title":"Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing.","volume":"1863","author":"van Kuilenburg","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"R8-20261002","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/cpt.210","article-title":"Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil\/uracil ratio.","volume":"99","author":"Thomas","year":"2016","journal-title":"Clin Pharmacol Ther"},{"key":"R9-20261002","doi-asserted-by":"crossref","first-page":"W140","DOI":"10.1093\/nar\/gkae413","article-title":"ProtVar: mapping and contextualizing human missense variation.","volume":"52","author":"Stephenson","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"R10-20261002","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3390\/pharmaceutics17010008","article-title":"The frequency of DPYD c.557A>G in the Dominican population and its association with African ancestry.","volume":"17","author":"Guevara","year":"2024","journal-title":"Pharmaceutics"},{"key":"R11-20261002","first-page":"1603","article-title":"Ethnic diversity of DPD activity and the DPYD gene: review of the literature.","volume":"14","author":"White","year":"2021","journal-title":"Pharmgenomics Pers 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History"}},{"value":"2026-07-09","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}