IMPORTANCIA CLÍNICA Y FARMACOGENÉTICA DEL GEN DPYD EN EL TRATAMIENTO DE FLUOROPIRIMIDINAS EN ONCOLOGÍA CLÍNICA
Clinical and pharmacogenetic importance of the DPYD gene in the treatment of fluoropyrimidines in clinical oncology
Palabras clave:
fluorouracilo, capecitabina, farmacogenética, quimioterapiaResumen
Introducción: Las fluoropirimidinas (5-fluorouracilo/capecitabina) son quimioterápicos fundamentales en oncología. La enzima dihidropirimidina deshidrogenasa (DPD), codificada por el gen DPYD, metaboliza el 80-85% del fármaco. Variantes en DPYD reducen la actividad enzimática, llevando a la acumulación tóxica del fármaco, con toxicidad grave (10-40% de pacientes) y desenlaces fatales en el 1%. Objetivo: Sintetizar la evidencia científica actual sobre la relevancia clínica del genotipado del gen DPYD para optimizar la seguridad y eficacia del tratamiento quimioterapéutico. Metodología: Se realizó una revisión bibliográfica siguiendo principios PRISMA. Se buscó en PharmGKB, PubMed y ScienceDirect usando términos como "fluorouracilo", "capecitabina", "farmacogenética", "DPYD". Se incluyeron artículos en inglés y español, de acceso abierto, entre 2020-2025. Se excluyeron cartas, resúmenes y publicaciones de pago. Resultados: Se identificaron cuatro variantes críticas (c.1905+1G>A, c.1679T>G, c.2846A>T y c.1236G>A/HapB3) asociadas a un riesgo elevado de neutropenia, mucositis, diarrea severa y riesgo de mortalidad. El genotipado preventivo permite clasificar a los pacientes según su fenotipo metabólico y ajustar la dosis inicial entre un 25% y 50%. Discusión: La implementación del genotipado de DPYD reduce de manera efectiva la incidencia de toxicidad grave, mejorando el perfil de seguridad. Sin embargo, su adopción clínica es desigual, con limitaciones importantes en países en desarrollo debido a la falta de infraestructura, conocimiento y políticas de farmacogenómica. Conclusiones: La farmacogenética de DPYD es crucial para la seguridad en el uso de fluoropirimidinas, la genotipificación de variantes clave y el ajuste de dosis previenen toxicidades graves.
Descargas
Citas
1. Jurczyk M, Król M, Midro A, Kurnik-Łucka M, Poniatowski A, Gil K. Cardiotoxicity of Fluoropyrimidines: Epidemiology, Mechanisms, Diagnosis, and Management. J Clin Med [Internet]. 2021 Sep 27 [cited 2025 Nov 16];10(19):4426. Available from: https://www. mdpi.com/2077-0383/10/19/4426
2. Grumetti L, Lombardi R, Iannelli F, Pucci B, Avallone A, Di Gennaro E, et al. Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors. Cancers (Basel) [Internet]. 2022 Jan 29 [cited 2025 Nov 16];14(3):695. Available from: http://www.ncbi. nlm.nih.gov/pubmed/35158962
3. Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, et al. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol [Internet]. 2018 Nov 1 [cited 2025 Nov 16];19(11):1459–67. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/30348537
4. Peeters JGC, DuPage M. A PRC1-RNF2 knockout punch for cancer. Nat Cancer [Internet]. 2021 Oct 22 [cited 2025 Nov 16];2(10):996–7. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/35121885
5. Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, et al. 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. Lancet Oncol [Internet]. 2015 Dec 1 [cited 2025 Nov 16];16(16):1639–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26603945
6. De Falco V, Natalicchio MI, Napolitano S, Coppola N, Conzo G, Martinelli E, et al. A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant. Medicine [Internet]. 2019 May 1 [cited 2025 Nov 16];98(21):e15759. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/31124962
7. Zamora M G, López-Cepero L, Pazo Oubiña F D, De Hevia O, Noguera O, Ruiz A T, et al. Frecuencia e impacto clínico de las variantes
del gen de la DPYD. ILAPHAR | Revista de la OFIL [Internet]. 2023 Oct 2 [cited 2025 Nov 16]; Available from: https://www.ilaphar.org/
frecuencia-e-impacto-clinico-de-las-variantesdel-gen-de-la-dpyd/
8. Clinical Pharmacogenetics Implementation Consortium (CPIC). CPIC® Guideline for Fluoropyrimidines and DPYD [Internet]. 2024 [actualizado 2024 Mar; citado 2025 Nov 16]. Disponible en: https://cpicpgx.org/guidelines/ guideline-for-fluoropyrimidines-and-dpyd/
9. European Medicines Agency (EMA). EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine [Internet]. Amsterdam: EMA; 2020 [actualizado 2023 Dic; citado 2025 Nov 16]. Disponible en: https://www.ema. europa.eu/en/news/ema-recommendationsdpd-testing-prior-treatment-fluorouracilcapecitabine-tegafur-and-flucytosine
10. Lunenburg CATC, van der Wouden CH, Nijenhuis M, Crommentuijn-van Rhenen MH, de Boer-Veger NJ, Buunk AM, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet [Internet]. 2020 Apr 19 [cited 2025 Nov 16];28(4):508–17. Available from: http://www. ncbi.nlm.nih.gov/pubmed/31745289
11. Paulsen NH, Qvortrup C, Vojdeman FJ, Plomgaard P, Andersen SE, Ramlov A, et al. Dihydropyrimidine dehydrogenase (DPD) genotype and phenotype among Danish cancer patients: prevalence and correlation between DPYD-genotype variants and P-uracil
concentrations. Acta Oncol [Internet]. 2022 Nov 2 [cited 2025 Nov 16];61(11):1400–5. Available from: http://www.ncbi.nlm.nih.gov/
pubmed/36256873
12. Saif MW, Hachem H, Purvey S, Hamal R, Zhang L, Siddiqui NS, et al. Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice. Arch Pharmacol Ther [Internet]. 2020 Dec 31 [cited 2025 Nov 16];2(1):6–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/33283204
13. Riera P, Riba M, Bernal S, Virgili AC, Páez D, Moreno ME. Frequency and clinical relevance of DPYD genetic variants in gastrointestinal
cancer patients. Farm Hosp [Internet]. 2021 Dec 21 [cited 2025 Nov 16];45(7):5–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35379107
14. Otero-Torres S, Rodríguez-Mauriz R, Fort-Casamartina E, Clopés-Estela A, Soler-Rotllant F, Fontanals-Martínez S, et al. DPYD Genotyping, Fluoropyrimidine Dosage and Toxicity: An Umbrella Review of Systematic Reviews. Pharmaceuticals [Internet]. 2025 May 15 [cited 2025 Nov 16];18(5):727. Available from: https://www.mdpi.com/1424-8247/18/5/727
15. Thomas F, Hennebelle I, Delmas C, Lochon I, Dhelens C, Garnier Tixidre C, et al. Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/ uracil ratio. Clin Pharmacol Ther [Internet]. 2016 Feb 1 [cited 2025 Nov 16];99(2):235–42. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/26265035
16. De Matti E, Roncato R, Dalle Fratte C, Ecca F, Toffoli G, Cecchin E. The use of pharmacogenetics to increase the safety of colorectal cancer patients treatedwith fluoropyrimidines. Cancer Drug Resistance [Internet]. 2019 Mar 19 [cited 2025 Nov 16];2(1):116–30. Available from: https://www.oaepublish.com/articles/cdr.2019.04
17. Pruebas genéticas - Dihidropirimidina deshidrogenasa, Deficiencia de …, (Dihydropyrimidine dehydrogenase deficiency) - Gen DPYD. - IVAMI [Internet]. [cited 2025 Nov 16]. Available from: https://www.ivami.com/es/pruebas-geneticas-mutaciones-degenes-humanos-enfermedades-neoplasiasy-farmacogenetica/2392-pruebas-geneticasdihidropirimidina-deshidrogenasa-deficienciade-dihydropyrimidine-dehydrogenasedeficiency-gen-dpyd
18. Sánchez-Bayona R, Catalán C, Cobos MA, Bergamino M. Pharmacogenomics in Solid Tumors: A Comprehensive Review of Genetic Variability and Its Clinical Implications. Cancers (Basel) [Internet]. 2025 Mar 7 [cited 2025 Nov 16];17(6):913. Available from: https://www.
mdpi.com/2072-6694/17/6/913
19. Montella A, Cantalupo S, D’Alterio G, Damiano V, Iolascon A, Capasso M. Improving single nucleotide polymorphisms genotyping
accuracy for dihydropyrimidine dehydrogenase testing in pharmacogenetics. Explor Target Antitumor Ther [Internet]. 2024 Apr 24 [cited
2025 Nov 16];5(2):374–83. Available from: https://www.explorationpub.com/Journals/etat/Article/1002223
20. Hamzic S, Aebi S, Joerger M, Montemurro M, Ansari M, Amstutz U, et al. Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy. Swiss Med Wkly [Internet]. 2020 Nov 16 [cited 2025 Nov 16];150(4748):w20375. Available from: http://www.ncbi.nlm.nih.gov/pubmed/33232506
21. Fiebrich-Westra HB, Haroun C, van der Galiën R, den Besten-Bertholee D, Deenen MJ, Moes DJAR, et al. Precision Treatment of Patients With GI Cancer Using Preemptive DPYD Genotyping/Phenotyping Plus Pharmacokinetic-Guided Dosing of 5-Fluorouracil. JCO Precis Oncol [Internet]. 2025 Jun [cited 2025 Nov 16];9(9):e2500062. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/40479625
22. Bignucolo A, De Mattia E, Roncato R, Peruzzi E, Scarabel L, D’Andrea M, et al. Ten-year experience with pharmacogenetic testing for DPYD in a national cancer center in Italy: Lessons learned on the path to implementation. Front Pharmacol [Internet]. 2023 [cited 2025 Nov 16];14:1199462. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/37256229
23. rs56038477 (SNP) - Datos de fenotipo - Homo sapiens - Navegador genómico Ensembl 115 [Internet]. [cited 2025 Nov 16]. Available from: https://www.ensembl.org/Homo_sapiens/ Variation/Phenotype?db=core;r=1:9757336397574363;v=rs56038477;vdb=variation
;vf=898209
24. Turner AJ, Haidar CE, Yang W, Boone EC, Offer SM, Empey PE, et al. Updated DPYD HapB3 haplotype structure and implications
for pharmacogenomic testing. Clin Transl Sci [Internet]. 2024 Jan 10 [cited 2025 Nov 16];17(1):e13699. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/38129972
25. Llorente AA. CURSO MONITORIZACIÓN DE FÁRMACOS OBJETIVOS ESPECÍFICOS. Sociedad Española de Medicina de Laboratorio. 2022;
26. Relevancia clínica de las variantes DPYD c.1679T>G, c.1236G>A/HapB3 y c.1601G>A como predictores de toxicidad grave asociada a
fluoropirimidinas: una revisión sistemática y un metaanálisis de datos individuales de pacientes - [Internet]. [cited 2025 Nov 16]. Available from: https://www.medicinesresources.n h s . u k / e n / M e d i c i n e s - A w a r e n e s s /Systematic-Review/Systematic-Reviews/Clinical-relevance-of-DPYD-variants-c1679TGc1236GAHapB3-and-c1601GA-as-predictors-ofsevere-fluoropyrimidine-associated-toxicity--635812182/?id=801524
27. NM_000110.4(DPYD):c.1679T>G (p.Ile560Ser) AND Dihydropyrimidine dehydrogenase deficiency - ClinVar - NCBI [Internet]. [cited
2025 Nov 16]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/RCV000410952/
28. Díaz-Villamarín X, Martínez-Pérez M, NietoSánchez MT, Ruiz-Tueros G, Fernández-Varón E, Torres-García A, et al. Novel Genetic Variants Explaining Severe Adverse Drug Events after
Clinical Implementation of DPYD GenotypeGuided Therapy with Fluoropyrimidines: An Observational Study. Pharmaceutics [Internet]. 2024 Jul 19 [cited 2025 Nov 16];16(7):956. Available from: https://www. mdpi.com/1999-4923/16/7/956
29. Ardizzone A, Bulzomì M, De Luca F, Silvestris N, Esposito E, Capra AP. Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients. Curr Issues Mol Biol [Internet]. 2024 Sep 4 [cited 2025 Nov 16];46(9):9831– 43. Available from: https://www.mdpi. com/1467-3045/46/9/584
30. Ho TT, Smith DM, Aquilante CL, Cicali EJ, El Rouby N, Hertz DL, et al. A Guide for Implementing DPYD Genotyping for Systemic Fluoropyrimidines into Clinical Practice. Clin Pharmacol Ther [Internet]. 2025 May 1 [cited 2025 Nov 16];117(5):1194–208. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/39887719
31. Shamaei Zadeh A, Roberts D, Williams A, Pandey D, Villano JL. Dihydropyrimidine toxicity: importance of genetic testing. Cancer Chemother Pharmacol [Internet]. 2025 Jan 18 [cited 2025 Nov 16];95(1):26. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/39825952
32. de Moraes FCA, Almeida Barbosa AB, Sano VKT, Kelly FA, Burbano RMR. Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis. BMC Cancer [Internet]. 2024 Sep 30 [cited 2025 Nov 16];24(1):1210. Available from: https://bmccancer.biomedcentral.com/ articles/10.1186/s12885-024-12981-5
33. Ho TT, Smith DM, Aquilante CL, Cicali EJ, El Rouby N, Hertz DL, et al. A Guide for Implementing DPYD Genotyping for Systemic Fluoropyrimidines into Clinical Practice. Clin Pharmacol Ther [Internet]. 2025 May 31 [cited 2025 Nov 16];117(5):1194–208. Available from: https://ascpt.onlinelibrary.wiley.com/ doi/10.1002/cpt.3567
34. Ly RC, Schmidt RE, Kiel PJ, Pratt VM, Schneider BP, Radovich M, et al. Severe Capecitabine Toxicity Associated With a Rare DPYD Variant Identified Through Whole-Genome Sequencing. JCO Precis Oncol [Internet]. 2020 Nov [cited 2025 Nov 16];4(4):632–8. Available from: https://ascopubs.org/doi/10.1200/PO.20.00067
35. Lau DK, Fong C, Arouri F, Cortez L, Katifi H, Gonzalez-Exposito R, et al. Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre. BMC Cancer [Internet]. 2023 Apr 26 [cited 2025 Nov 16];23(1):380. Available from: http://www.ncbi. nlm.nih.gov/pubmed/37101114
36. Rosas-Alonso R, Salas NR, Wert PP, Hoyo A, Martin-López S, Martínez-Pérez D, et al. DPYDguided fluoropyrimidine dose adjustment in colorectal cancer DPYD carriers: start slower to finish stronger. Front Pharmacol [Internet]. 2025 Sep 18 [cited 2025 Nov 16];16:1645188. Available from: https://www.frontiersin.org/ articles/10.3389/fphar.2025.1645188/full
37. García-Alfonso P, Saiz-Rodríguez M, Mondéjar R, Salazar J, Páez D, Borobia AM, et al. Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer
patients who are candidates for treatment with fluoropyrimidines. Clin Transl Oncol [Internet]. 2022 Mar 1 [cited 2025 Nov 16];24(3):483–94. Available from: http://www.ncbi.nlm.nih.gov/pubmed/34773566
Publicado
Cómo citar
Número
Sección
Licencia
Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial 4.0.
