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Clinical Implementation of Rare and Novel DPYD Variants for Personalizing Fluoropyrimidine Treatment: Challenges and Opportunities.
De Mattia, Elena; Milan, Noemi; Assaraf, Yehuda G; Toffoli, Giuseppe; Cecchin, Erika.
Afiliación
  • De Mattia E; Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano (PN), Italy.
  • Milan N; Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano (PN), Italy.
  • Assaraf YG; The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
  • Toffoli G; Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano (PN), Italy.
  • Cecchin E; Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano (PN), Italy.
Int J Biol Sci ; 20(10): 3742-3759, 2024.
Article en En | MEDLINE | ID: mdl-39113696
ABSTRACT
Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (DPYD) (DPYD*2A, DPYD*13, c.2846A > T, c.1129-5923C > G) prior to FL treatment, is recommended by scientific consortia (e.g., CPIC, DPWG) and drug regulatory agencies (e.g., EMA). However, this panel identifies < 20% of patients at risk of severe FL-related toxicity. Cumulative recent evidence highlights the potential clinical value of rare (minor allele frequency < 1%) and novel DPYD genetic variants for identifying an additional fraction of DPD-deficient patients at increased risk of severe FL-related toxicity. In this review, we aimed to comprehensively describe the available evidence regarding the potential clinical predictive role of novel and rare DPYD variants as toxicity markers in FL-treated patients, and to discuss the challenges and opportunities in tailoring FL treatment based upon clinical application of such markers. Although we must overcome existing barriers to the clinical implementation, the available data support that comprehensive assessment of the DPYD sequence, including rare and novel genetic variants, may significantly enhance the pre-emptive identification of at-risk patients, compared to the current targeted approach.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dihidrouracilo Deshidrogenasa (NADP) / Medicina de Precisión Límite: Humans Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Australia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dihidrouracilo Deshidrogenasa (NADP) / Medicina de Precisión Límite: Humans Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Australia