{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T21:40:55Z","timestamp":1773092455324,"version":"3.50.1"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec>\n            <jats:title>Objectives<\/jats:title>\n            <jats:p>Genetic variants in the <jats:italic toggle=\"yes\">dihydropyrimidine dehydrogenase (DPYD<\/jats:italic>) gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity and can cause severe fluoropyrimidine-related toxicity. We assessed the frequency of the four most common and well-established <jats:italic toggle=\"yes\">DPYD<\/jats:italic> variants associated with fluoropyrimidine toxicity and implemented a relatively low-cost and high-throughput genotyping assay for their detection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This study includes 457 patients that were genotyped for the <jats:italic toggle=\"yes\">DPYD<\/jats:italic> c.1129-5923C&gt;G, c.1679T&gt;G, c.1905\u2009+\u20091G&gt;A and c.2846A&gt;T variants, either by Sanger sequencing or kompetitive allele specific PCR (KASP) technology. Of these, 172 patients presented toxicity during treatment with fluoropyrimidines (post-treatment group), and 285 were tested before treatment (pretreatment group).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Heterozygous <jats:italic toggle=\"yes\">DPYD<\/jats:italic> variants were identified in 7.4% of the entire series of 457 patients, being the c.2846A&gt;T the most frequent variant. In the post-treatment group, 15.7% of the patients presented <jats:italic toggle=\"yes\">DPYD<\/jats:italic> variants, whereas only 2.5% of the patients in the pretreatment group presented a variant. The KASP assays designed in this study presented 100% genotype concordance with the results obtained by Sanger sequencing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The combined assessment of the four <jats:italic toggle=\"yes\">DPYD<\/jats:italic> variants in our population increases the identification of patients at high risk for developing fluoropyrimidine toxicity, supporting the upfront routine implementation of <jats:italic toggle=\"yes\">DPYD<\/jats:italic> variant genotyping. Furthermore, the KASP genotyping assay described in this study presents a rapid turnaround time and relatively low cost, making upfront <jats:italic toggle=\"yes\">DPYD<\/jats:italic> screening feasible in clinical practice.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000505","type":"journal-article","created":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T14:23:35Z","timestamp":1692800615000},"page":"165-171","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Implementation of upfront DPYD genotyping with a low-cost and high-throughput assay to guide fluoropyrimidine treatment in cancer patients"],"prefix":"10.1097","volume":"33","author":[{"given":"Manuela","family":"Pinheiro","sequence":"first","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"}]},{"given":"Ana","family":"Peixoto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Patr\u00edcia","family":"Rocha","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Catarina","family":"Santos","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Carla","family":"Escudeiro","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Isabel","family":"Veiga","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Miguel","family":"Porto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"}]},{"given":"Joana","family":"Guerra","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"}]},{"given":"Ana","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Carla","family":"Pinto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"}]},{"given":"Patr\u00edcia","family":"Arinto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"}]},{"given":"Adriana","family":"Resende","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"}]},{"given":"Manuel R.","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, Porto, Portugal"},{"name":"School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal"}]}],"member":"276","published-online":{"date-parts":[[2023,8,24]]},"reference":[{"key":"R1-20250808","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1200\/JCO.2001.19.8.2282","article-title":"Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients 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dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.","volume":"136","author":"Froehlich","year":"2015","journal-title":"Int J Cancer"},{"key":"R5-20250808","doi-asserted-by":"crossref","first-page":"e0175998","DOI":"10.1371\/journal.pone.0175998","article-title":"New advances in DPYD genotype and risk of severe toxicity under capecitabine.","volume":"12","author":"Etienne-Grimaldi","year":"2017","journal-title":"PLoS One"},{"key":"R6-20250808","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ejca.2019.09.028","article-title":"Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: a real-life evaluation in France.","volume":"124","author":"Barin-Le Guellec","year":"2020","journal-title":"Eur J Cancer"},{"key":"R7-20250808","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2165\/00003088-198916040-00002","article-title":"Clinical pharmacology of 5-fluorouracil.","volume":"16","author":"Diasio","year":"1989","journal-title":"Clin Pharmacokinet"},{"key":"R8-20250808","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/sj.bjc.6690098","article-title":"Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity.","volume":"79","author":"Milano","year":"1999","journal-title":"Br J Cancer"},{"key":"R9-20250808","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/ijc.10599","article-title":"Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14\u2009+\u20091g>a mutation.","volume":"101","author":"Van Kuilenburg","year":"2002","journal-title":"Int J Cancer"},{"key":"R10-20250808","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1002\/ijc.29654","article-title":"Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines.","volume":"137","author":"Toffoli","year":"2015","journal-title":"Int J Cancer"},{"key":"R11-20250808","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1016\/S0959-8049(97)00261-X","article-title":"Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity.","volume":"33","author":"Van Kuilenburg","year":"1997","journal-title":"Eur J Cancer"},{"key":"R12-20250808","first-page":"768","article-title":"Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype.","volume":"8","author":"Johnson","year":"2002","journal-title":"Clin Cancer Res"},{"key":"R13-20250808","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1158\/0008-5472.CAN-12-3858","article-title":"Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity.","volume":"73","author":"Offer","year":"2013","journal-title":"Cancer Res"},{"key":"R14-20250808","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/cpt.685","article-title":"Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity.","volume":"102","author":"Nie","year":"2017","journal-title":"Clin Pharmacol Ther"},{"key":"R15-20250808","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/FPC.0000000000000197","article-title":"Association between DPYD c.1129-5923 C>G\/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).","volume":"26","author":"Lee","year":"2016","journal-title":"Pharmacogenet Genomics"},{"key":"R16-20250808","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":"R17-20250808","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S1470-2045(18)30686-7","article-title":"DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.","volume":"19","author":"Henricks","year":"2018","journal-title":"Lancet Oncol"},{"key":"R18-20250808","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1111\/bcp.14742","article-title":"Haplotype structure defines effects of common DPYD variants c.85T > C (rs1801265) and c.496A > G (rs2297595) on dihydropyrimidine dehydrogenase activity: implication for 5-fluorouracil toxicity.","volume":"87","author":"Hamzic","year":"2021","journal-title":"Br J Clin Pharmacol"},{"key":"R19-20250808","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/cpt.2350","article-title":"An evidence-based framework for evaluating pharmacogenomics knowledge for personalized medicine.","volume":"110","author":"Whirl-Carrillo","year":"2021","journal-title":"Clin Pharmacol Ther"},{"key":"R20-20250808","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1177\/10781552211049144","article-title":"Potential added value of combined DPYD\/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity.","volume":"29","author":"Ockeloen","year":"2023","journal-title":"J Oncol Pharm Pract"},{"key":"R21-20250808","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.bulcan.2018.02.001","article-title":"D\u00e9pistage du d\u00e9ficit en dihydropyrimidine d\u00e9shydrog\u00e9nase (DPD) et s\u00e9curisation des chimioth\u00e9rapies \u00e0 base de fluoropyrimidines: mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx [Dihydropyrimidine d\u00e9hydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: update and recommendations of the French GPCO-Unicancer and RNPGx networks].","volume":"105","author":"Loriot","year":"2018","journal-title":"Bull Cancer"},{"key":"R23-20250808","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41431-019-0540-0","article-title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines.","volume":"28","author":"Lunenburg","year":"2020","journal-title":"Eur J Hum Genet"},{"key":"R24-20250808","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1158\/1535-7163.MCT-06-0327","article-title":"Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance.","volume":"5","author":"Morel","year":"2006","journal-title":"Mol Cancer Ther"},{"key":"R25-20250808","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00280-009-1147-x","article-title":"The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients.","volume":"65","author":"Loganayagam","year":"2010","journal-title":"Cancer Chemother Pharmacol"},{"key":"R26-20250808","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/clpt.2013.172","article-title":"Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing.","volume":"94","author":"Caudle","year":"2013","journal-title":"Clin Pharmacol Ther"},{"key":"R27-20250808","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1200\/JCO.2015.63.1325","article-title":"Upfront Genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis.","volume":"34","author":"Deenen","year":"2016","journal-title":"J Clin Oncol"},{"key":"R28-20250808","doi-asserted-by":"crossref","first-page":"885259","DOI":"10.3389\/fphar.2022.885259","article-title":"Clinical Implementation of DPYD pharmacogenetic testing to prevent early-onset fluoropyrimidine-related toxicity in cancer patients in Switzerland.","volume":"13","author":"Begr\u00e9","year":"2022","journal-title":"Front Pharmacol"},{"key":"R29-20250808","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1186\/s12885-023-10857-8","article-title":"Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre.","volume":"23","author":"Lau","year":"2023","journal-title":"BMC Cancer"},{"key":"R30-20250808","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/01.GIM.0000118061.66602.A5","article-title":"Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients.","volume":"6","author":"Salgueiro","year":"2004","journal-title":"Genet 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gene.","volume":"43","author":"Ofverholm","year":"2010","journal-title":"Clin Biochem"},{"key":"R37-20250808","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s10549-019-05144-9","article-title":"Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients.","volume":"175","author":"Stavraka","year":"2019","journal-title":"Breast Cancer Res Treat"},{"key":"R38-20250808","doi-asserted-by":"crossref","first-page":"e597","DOI":"10.1002\/onco.13626","article-title":"Implementing DPYD*2A Genotyping in clinical practice: the Quebec, Canada, experience.","volume":"26","author":"Jolivet","year":"2021","journal-title":"Oncologist"},{"key":"R39-20250808","doi-asserted-by":"crossref","first-page":"113644","DOI":"10.1016\/j.biopha.2022.113644","article-title":"Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk.","volume":"154","author":"De Mattia","year":"2022","journal-title":"Biomed 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