{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:51:13Z","timestamp":1791352273670,"version":"4.3.1"},"reference-count":50,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    The chemotherapeutic 5\u2010fluorouracil (5\u2010FU) is commonly used to treat solid tumors, especially colorectal cancer. Deleterious variants in\n                    <jats:italic>DPYD,<\/jats:italic>\n                    which encodes dihydropyrimidine dehydrogenase (DPD), are strongly associated with severe and potentially lethal 5\u2010FU toxicity. Phenotypic assays for DPD function have been proposed as alternative or complementary approaches to identify DPD deficiencies with the rationale that they may capture unrecognized causes. These assays include the direct measurement of DPD activity in peripheral blood mononuclear cell (PBMC) lysates and measuring plasma metabolites uracil (U), dihydrouracil (UH\n                    <jats:sub>2<\/jats:sub>\n                    ), and the dihydrouracil\/uracil (UH\n                    <jats:sub>2<\/jats:sub>\n                    :U) ratio. We evaluated correlations between PBMC DPD activity and plasma metabolite measures in matched samples from 203 patients with available\n                    <jats:italic>DPYD<\/jats:italic>\n                    exome sequencing data. We also compared the ability of phenotypic measures to identify carriers of deleterious\n                    <jats:italic>DPYD<\/jats:italic>\n                    variants. In addition to established high\u2010risk variants, we identified three rare\n                    <jats:italic>DPYD<\/jats:italic>\n                    variants predicted to be deleterious: c.274C&gt;G, c.966C&gt;A, and c.1435G&gt;A. Collectively, these variants were associated with impaired DPD function with effect sizes comparable to well\u2010studied toxicity\u2010associated variants. At the population level and within carriers of specific genotypes, weak but significant correlations were observed between PBMC DPD activity and either UH\n                    <jats:sub>2<\/jats:sub>\n                    :U ratio or U level. These findings suggest that although phenotypic assays can detect severe DPD deficiency, high variability limits their utility as standalone diagnostic tools. Integration with genetic testing may provide a more robust pretreatment risk assessment strategy.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70511","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:28:16Z","timestamp":1791350896000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dihydropyrimidine Dehydrogenase Genotype\u2013Phenotype Correlations in Plasma and Peripheral Blood Mononuclear Cells"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8798-8706","authenticated-orcid":false,"given":"Brianna M.","family":"Bembenek","sequence":"first","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Pathology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3316-0022","authenticated-orcid":false,"given":"Seid","family":"Hamzic","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Inselspital, Bern University Hospital University of Bern  Bern Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5290-9169","authenticated-orcid":false,"given":"Kelly J.","family":"Bouchonville","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0889-8922","authenticated-orcid":false,"given":"Carlo R.","family":"Largiad\u00e8r","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Inselspital, Bern University Hospital University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-9678","authenticated-orcid":false,"given":"Steven M.","family":"Offer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1200\/JCO.1998.16.11.3537","article-title":"Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors","volume":"16","author":"Meta\u2010Analysis Group In Cancer","year":"1998","journal-title":"J. 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