{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:27:00Z","timestamp":1790630820560,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII)","award":["PMP22\/00056"],"award-info":[{"award-number":["PMP22\/00056"]}]},{"name":"European Union funds (NextGen)","award":["PMP22\/00056"],"award-info":[{"award-number":["PMP22\/00056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fluoropyrimidine derivatives can cause severe toxicity in patients with DPD deficiency. Regulatory agencies, such as the European Medicines Agency (EMA), recommend pre-emptive genotyping of the HapB3 haplotype, along with other variants. Historically, the two main HapB3 variants, the benign c.1236G&gt;A and the pathogenic c.1129-5923C&gt;G, have been assumed to be in complete linkage disequilibrium. Recent findings contradict this assumption, questioning the reliability of the HapB3 analysis through c.1236G&gt;A, which could directly impact patient safety. The aim of this study is to assess the linkage disequilibrium between the c.1236G&gt;A and c.1129-5923C&gt;G variants, with the ultimate goal of revising genotyping guidelines. A total of 46 patients already heterozygous for the c.1236G&gt;A variant have been carefully reviewed for the c.1129-5923C&gt;G variant. From the 46 patients analyzed, 45 maintain complete linkage disequilibrium between both variants. However, there is one patient where this linkage disequilibrium is not complete, being heterozygous for c.1236G&gt;A and homozygous for c.1129-5923C&gt;G. These findings challenge the validity of c.1236G&gt;A as a surrogate marker for pathogenic variant c.1129-5923C&gt;G. This article highlights the need for a review of the recommendations of the EMA and suggests laboratories to analyze both variants, or at least the pathogenic one, to ensure accurate therapeutic decisions.<\/jats:p>","DOI":"10.3390\/ijms26178136","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T12:31:26Z","timestamp":1755865886000},"page":"8136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Lack of Complete Linkage Disequilibrium Between c.1236G&gt;A and c.1129-5923C&gt;G HapB3 Variants of DPYD: A Call to Revise European Pharmacogenetic Guidelines"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-6915","authenticated-orcid":false,"given":"Almudena","family":"Gil-Rodriguez","sequence":"first","affiliation":[{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Genomics and Bioinformatics Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1623-1110","authenticated-orcid":false,"given":"Sheila","family":"Recarey-Rama","sequence":"additional","affiliation":[{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Genomics and Bioinformatics Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4630-5830","authenticated-orcid":false,"given":"Ana","family":"Fern\u00e1ndez Montes","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, University Hospital Complex of Ourense (CHUO), 32005 Ourense, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Rodr\u00edguez-Viyuela","sequence":"additional","affiliation":[{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Genomics and Bioinformatics Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6895-4140","authenticated-orcid":false,"given":"Francisco","family":"Barros","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Galician Public Foundation of Genomic Medicine (FPGMX), Galician Healthcare Service (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1085-8986","authenticated-orcid":false,"given":"Angel","family":"Carracedo","sequence":"additional","affiliation":[{"name":"Genomics and Bioinformatics Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Galician Public Foundation of Genomic Medicine (FPGMX), Galician Healthcare Service (SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Genetics Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olalla","family":"Maro\u00f1as","sequence":"additional","affiliation":[{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Genomics and Bioinformatics Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Galician Public Foundation of Genomic Medicine (FPGMX), Galician Healthcare Service (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sim\u00f5es, A.R., Fern\u00e1ndez-Rozadilla, C., Maro\u00f1as, O., and Carracedo, \u00c1. (2020). The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040237"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1093\/annonc\/mdx411","article-title":"DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: Call for a drug label update","volume":"28","author":"Henricks","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_3","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":"ref_4","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/S1470-2045(15)00286-7","article-title":"Clinical relevance of DPYD variants c.1679T>G, c.1236G>A\/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: A systematic review and meta-analysis of individual patient data","volume":"16","author":"Meulendijks","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1006\/geno.1998.5379","article-title":"Characterization of the human dihydropyrimidine dehydrogenase gene","volume":"51","author":"Wei","year":"1998","journal-title":"Genomics"},{"key":"ref_6","first-page":"1660","article-title":"Structural organization of the human dihydropyrimidine dehydrogenase gene","volume":"57","author":"Johnson","year":"1997","journal-title":"Cancer Res."},{"key":"ref_7","unstructured":"(2025, January 12). PharmGKB. Available online: https:\/\/www.pharmgkb.org\/."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"931","DOI":"10.2217\/pgs.09.28","article-title":"Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: A haplotype assessment","volume":"10","author":"Amstutz","year":"2009","journal-title":"Pharmacogenomics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141, 456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/ijc.29025","article-title":"Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity","volume":"136","author":"Froehlich","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_11","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":"ref_12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.15386\/mpr-1564","article-title":"A review on the importance of genotyping and phenotyping in fluoropyrimidine treatment","volume":"93","author":"Deac","year":"2020","journal-title":"Med. Pharm. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gil-Rodriguez, A., Recarey-Rama, S., Rodr\u00edguez-Viyuela, A., Cruz, R., Barros, F., Carracedo, A., and Maro\u00f1as, O. (2025). Differences in DPYD Population Frequencies Observed in Galicians Compared to Europeans and Spanish from PhotoDPYD Study. Pharmaceuticals, 18.","DOI":"10.3390\/ph18040515"},{"key":"ref_14","unstructured":"PharmGKB (2025, March 30). DPYD Frequency Table. Gene-Specific Information. Tables for DPYD. Available online: https:\/\/www.pharmgkb.org\/page\/dpydRefMaterials."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1200\/JCO.2006.10.4182","article-title":"Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: A prospective clinical trial by the German 5-FU Toxicity Study Group","volume":"26","author":"Schwab","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5886","DOI":"10.1158\/1078-0432.CCR-04-1784","article-title":"Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals","volume":"11","author":"Seck","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00439-010-0879-3","article-title":"Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity","volume":"128","author":"Meijer","year":"2010","journal-title":"Hum. Genet."},{"key":"ref_18","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":"ref_19","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s00280-016-3137-0","article-title":"Patients homozygous for DPYD c.1129-5923C>G\/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines","volume":"78","author":"Meulendijks","year":"2016","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1093\/bioinformatics\/btv402","article-title":"LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants","volume":"31","author":"Machiela","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1126\/science.1069424","article-title":"The structure of haplotype blocks in the human genome","volume":"296","author":"Gabriel","year":"2002","journal-title":"Science"},{"key":"ref_22","unstructured":"Ensembl (2025, March 26). Linkage Disequilibrium Data-Ensembl Genome Browser 113. Available online: https:\/\/www.ensembl.org\/Help\/View?id=197."},{"key":"ref_23","unstructured":"NIH (2025, January 27). LDlink-National Institutes of Health, Available online: https:\/\/ldlink.nih.gov\/?tab=home."},{"key":"ref_24","unstructured":"gnomAD (2025, February 20). 1-97573863-C-T|gnomAD v4.1.0. Available online: https:\/\/gnomad.broadinstitute.org\/variant\/1-97573863-C-T?dataset=gnomad_r4."},{"key":"ref_25","unstructured":"gnomAD (2025, February 20). 1-97579893-G-C|gnomAD v4.1.0. Available online: https:\/\/gnomad.broadinstitute.org\/variant\/1-97579893-G-C?dataset=gnomad_r4."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e13699","DOI":"10.1111\/cts.13699","article-title":"Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing","volume":"17","author":"Turner","year":"2024","journal-title":"Clin. Transl. Sci."},{"key":"ref_27","unstructured":"All of Us Research Program Genomics Investigators (2024). Genomic data in the All of Us Research Program. Nature, 627, 340\u2013346."},{"key":"ref_28","unstructured":"European Medicines Agency (EMA) (2025, January 11). EMA Recommendations on DPD Testing Prior to Treatment with Fluorouracil, Capecitabine, Tegafur and Flucytosine. Available online: https:\/\/www.ema.europa.eu\/en\/news\/ema-recommendations-dpd-testing-prior-treatment-fluorouracil-capecitabine-tegafur-flucytosine."},{"key":"ref_29","unstructured":"European Medicines Agency (EMA) (2025, March 28). Xeloda. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/xeloda."},{"key":"ref_30","unstructured":"Agencia Espa\u00f1ola de Medicamentos y Productos Sanitarios (2025, March 30). Fluorouracilo, Capecitabina, Tegafur y Flucitosina en Pacientes Con D\u00e9ficit de Dihidropirimidina Deshidrogenasa. Available online: https:\/\/www.aemps.gob.es\/informa\/fluorouracilo-capecitabina-tegafur-y-flucitosina-en-pacientes-con-deficit-de-dihidropirimidina-deshidrogenasa\/."},{"key":"ref_31","unstructured":"Agencia Espa\u00f1ola de Medicamentos y Productos Sanitarios (2025, June 17). Base de Datos de Biomarcadores Farmacogen\u00f3micos. 29 July 2024. Available online: https:\/\/www.aemps.gob.es\/medicamentos-de-uso-humano\/base-de-datos-de-biomarcadores-farmacogenomicos\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"w20375","DOI":"10.4414\/smw.2020.20375","article-title":"Fluoropyrimidine chemotherapy: Recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy","volume":"150","author":"Hamzic","year":"2020","journal-title":"Swiss. Med. Wkly."},{"key":"ref_33","unstructured":"PharmGKB (2025, March 22). Annotation of Swissmedic Label for Fluorouracil and DPYD. Available online: https:\/\/www.pharmgkb.org\/labelAnnotation\/PA166184450."},{"key":"ref_34","unstructured":"U.S. Food and Drug Administration (2025, May 09). FDA Approves Safety Labeling Changes Regarding DPD Deficiency for Fluorouracil Injection Products, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-safety-labeling-changes-regarding-dpd-deficiency-fluorouracil-injection-products."},{"key":"ref_35","unstructured":"U.S. Food and Drug Administration (2025, May 09). Safety Announcement: FDA Highlights Importance of DPD Deficiency Discussions with Patients Prior to Capecitabine or 5FU Treatment, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/safety-announcement-fda-highlights-importance-dpd-deficiency-discussions-patients-prior-capecitabine."},{"key":"ref_36","unstructured":"U.S. Food and Drug Administration (2025, January 11). Fluorouracil-Highlights of Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/210123s008lbl.pdf."},{"key":"ref_37","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":"ref_38","unstructured":"PharmGKB (2025, March 28). Annotation of AIOM Guideline for Capecitabine, Fluorouracil, Tegafur and DPYD. Available online: https:\/\/www.pharmgkb.org\/guidelineAnnotation\/PA166312801."},{"key":"ref_39","unstructured":"Association of Medical Oncology (AIOM) and the Italian Society of Pharmacology (SIF) (2025, January 11). Raccomandazioni Per Analisi Farmacogenetiche. Available online: https:\/\/www.aiom.it\/wp-content\/uploads\/2024\/11\/2024_Racc-analisi-farmacogenetiche-update.pdf."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.therap.2016.09.018","article-title":"Pharmacogenetics of antidepressant drugs: State of the art and clinical implementation\u2014Recommendations from the French National Network of Pharmacogenetics","volume":"72","author":"Quaranta","year":"2017","journal-title":"Therapie"},{"key":"ref_41","unstructured":"CPIC\u00ae (2025, January 11). Guideline for Fluoropyrimidines and DPYD. Available online: https:\/\/cpicpgx.org\/guidelines\/guideline-for-fluoropyrimidines-and-dpyd\/."},{"key":"ref_42","unstructured":"SEFF\u2014Sociedad Espa\u00f1ola de Farmacogen\u00e9tica y Farmacogen\u00f3mica (2025, March 28). Fluoropirimidinas-Recomendaciones Grupos de Trabajo de la SEFF. Available online: https:\/\/seff.es\/fluoropirimidinas\/."},{"key":"ref_43","unstructured":"Ministerio de Sanidad (2025, March 28). Cat\u00e1logo de Pruebas Gen\u00e9ticas y Gen\u00f3micas. Available online: https:\/\/cgen.sanidad.gob.es\/#\/mas-informacion."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1002\/cpt.2321","article-title":"Pharmacogene Variation Consortium: A Global Resource and Repository for Pharmacogene Variation","volume":"110","author":"Gaedigk","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_45","unstructured":"PharmVar (2025, January 27). Pharmacogene Variation Consortium (PharmVar). DPYD. Available online: https:\/\/www.pharmvar.org\/gene\/DPYD."},{"key":"ref_46","unstructured":"PharmVar (2025, January 27). Pharmacogene Variation Consortium. Gene Information Document-DPYD. Available online: https:\/\/a.storyblok.com\/f\/70677\/x\/7508dd7406\/gene-info_dpyd_v1-5.pdf."},{"key":"ref_47","unstructured":"PharmGKB (2025, January 11). Gene-Specific Information Tables for DPYD. Available online: https:\/\/www.pharmgkb.org\/page\/dpydRefMaterials."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.2217\/pgs.15.70","article-title":"Translating DPYD genotype into DPD phenotype: Using the DPYD gene activity score","volume":"16","author":"Henricks","year":"2015","journal-title":"Pharmacogenomics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ejca.2018.11.010","article-title":"A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy","volume":"107","author":"Henricks","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2500440","DOI":"10.1200\/PO-25-00440","article-title":"Reducing Fluorouracil Doses in Patients With Partial Dihydropyrimidine Dehydrogenase Deficiency Is a Treatment Safety Strategy, Not a Panacea of Precision Dosing","volume":"9","author":"Hertz","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_51","first-page":"e2500062","article-title":"Precision Treatment of Patients With GI Cancer Using Pre-emptive DPYD Genotyping\/Phenotyping Plus Pharmacokinetic-Guided Dosing of 5-Fluorouracil","volume":"9","author":"Haroun","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_52","first-page":"96822","article-title":"Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution","volume":"17","author":"Iengo","year":"2025","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9831","DOI":"10.3390\/cimb46090584","article-title":"Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients","volume":"46","author":"Ardizzone","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/1120009X.2025.2489837","article-title":"Application of dihydropyrimidine dehydrogenase deficiency testing for the prevention of fluoropyrimidine toxicity: A real-world experience in a Southern Italy cancer center","volume":"17","author":"Bianchino","year":"2025","journal-title":"J. Chemother."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Lau, D.K., Fong, C., Arouri, F., Cortez, L., Katifi, H., Gonzalez-Exposito, R., Razzaq, M.B., Li, S., Macklin-Doherty, A., and Hernandez, M.A. (2023). Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10857-8"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"100782","DOI":"10.1016\/j.esmoop.2023.100782","article-title":"Implementation and clinical benefit of DPYD genotyping in a Danish cancer population","volume":"8","author":"Paulsen","year":"2023","journal-title":"ESMO Open"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1080\/0284186X.2022.2132117","article-title":"Dihydropyrimidine dehydrogenase (DPD) genotype and phenotype among Danish cancer patients: Prevalence and correlation between DPYD-genotype variants and P-uracil concentrations","volume":"61","author":"Paulsen","year":"2022","journal-title":"Acta Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Gil-Rodr\u00edguez, A., Recarey-Rama, S., Rodr\u00edguez-Viyuela, A., Barros, F., Carracedo, A., and Maro\u00f1as, O. (2025). Balance of care activity after EMA recommendation for DPYD gene testing in Galicia. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1523536"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e304","DOI":"10.1093\/oncolo\/oyad077","article-title":"Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study","volume":"28","author":"Miarons","year":"2023","journal-title":"Oncologist"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ragia, G., Maslarinou, A., Atzemian, N., Biziota, E., Koukaki, T., Ioannou, C., Balgkouranidou, I., Kolios, G., Kakolyris, S., and Xenidis, N. (2023). Implementing pharmacogenetic testing in fluoropyrimidine-treated cancer patients: DPYD genotyping to guide chemotherapy dosing in Greece. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1248898"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/s41416-020-0962-z","article-title":"A comprehensive population-based study comparing the phenotype and genotype in a pretherapeutic screen of dihydropyrimidine dehydrogenase deficiency","volume":"123","author":"Pallet","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"de Moraes, F.C.A., de Almeida Barbosa, A.B., Sano, V.K.T., Kelly, F.A., and Burbano, R.M.R. (2024). Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: A meta-analysis and trial sequential analysis. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12981-5"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/s41416-023-02517-2","article-title":"Dihydropyrimidine dehydrogenase gene variants for predicting grade 4\u20135 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis","volume":"130","author":"Cozic","year":"2024","journal-title":"Br. J. Cancer"},{"key":"ref_64","unstructured":"ThermoFisher SCIENTIFIC (2025, April 09). Applied BiosystemsTM QuantStudioTM 12K Flex Real-Time PCR System OpenArray\u00ae Experiments. Available online: https:\/\/www.thermofisher.com\/content\/dam\/LifeTech\/migration\/files\/pcr\/pdfs.par.36605.file.dat\/4470935b.pdf."},{"key":"ref_65","unstructured":"Integrated DNA Technologies (2025, April 09). rhAmpTM SNP Genotyping System. Available online: https:\/\/eu.idtdna.com\/pages\/products\/qpcr-and-pcr\/genotyping\/rhamp-snp-genotyping."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8136\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:42Z","timestamp":1760034822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":65,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178136"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178136","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]}}}