Publication: Secuenciación masica de exomas y uso de TAG-SNPS en genes candidatos para identificar variantes genéticas asociadas a reacciones adversas severas a capecitabina
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2018-11-05
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Universidad Complutense de Madrid
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Abstract
Poder predecir el riesgo individual de toxicidad severa inducida por la quimioterapia basada en fluoropirimidinas sería un extraordinario avance en la personalización del tratamiento del cáncer colorrectal. Las fluoropirimidinas, principalmente 5-fluorouracilo y capecitabina, siguen constituyendo el pilar fundamental del tratamiento del cáncer colorrectal. Se ha demostrado que la genética del paciente es un factor fundamental en la forma en que dicho paciente responde a un fármaco. Hasta el momento, se han identificado algunos polimorfismos en genes implicados en la farmacocinética y farmacodinamia de las fluoropirimidinas. De hecho, ciertas guías de práctica clínica recomiendan el genotipado de algunas variantes en DPYD, el mayor metabolizador de 5-fluorouracilo, con el fin de estimar el riesgo de toxicidad. Sin embargo, el valor predictivo de estas pruebas genéticas sigue siendo claramente insuficiente, lo que dificulta su implantación real en la práctica clínica. Es, por tanto, necesario identificar nuevas variantes genéticas asociadas a toxicidad severa a fluoropirimidinas mediante nuevas aproximaciones para mejorar los test farmacogenéticos actuales. La selección de tag-SNPs y la secuenciación masiva de exomas podrían revelar nuevas variantes genéticas asociadas a toxicidad y/o validar las ya existentes, además de ofrecer una visión general del perfil farmacogenético...
To be able to predict the individual risk of severe toxicity induced by fluoropyrimidine-based chemotherapy would be an extraordinary step forward in personalizing colorectal cancer treatment. Fluoropyrimidines, primarily 5-fluorouracil and capecitabine, remain the cornerstone of colorectal cancer treatment. It has been demonstrated that the genetics of the patient is a fundamental factor on the type of response to the treatment. So far, some polymorphisms have been identified in genes involved in the pharmacokinetics and pharmacodynamics of fluoropyrimidines. In fact, certain clinical practice guidelines recommend prior genotyping of some variants in DPYD, the major metabolizer of 5-fluorouracil, in order to estimate the risk of its toxicity. However, the predictive value of these genetic tests remain clearly insufficient, making it difficult to fully implement it in clinical practice. It is therefore necessary to identify new genetic variants associated with severe toxicity to fluoropyrimidines by developing new approaches to improve current pharmacogenetic tests. The selection of tag-SNPs and the massive exome sequencing could reveal new genetic variants associated with toxicity and / or validate the existing ones, besides offering an overview of the pharmacogenetic profile...
To be able to predict the individual risk of severe toxicity induced by fluoropyrimidine-based chemotherapy would be an extraordinary step forward in personalizing colorectal cancer treatment. Fluoropyrimidines, primarily 5-fluorouracil and capecitabine, remain the cornerstone of colorectal cancer treatment. It has been demonstrated that the genetics of the patient is a fundamental factor on the type of response to the treatment. So far, some polymorphisms have been identified in genes involved in the pharmacokinetics and pharmacodynamics of fluoropyrimidines. In fact, certain clinical practice guidelines recommend prior genotyping of some variants in DPYD, the major metabolizer of 5-fluorouracil, in order to estimate the risk of its toxicity. However, the predictive value of these genetic tests remain clearly insufficient, making it difficult to fully implement it in clinical practice. It is therefore necessary to identify new genetic variants associated with severe toxicity to fluoropyrimidines by developing new approaches to improve current pharmacogenetic tests. The selection of tag-SNPs and the massive exome sequencing could reveal new genetic variants associated with toxicity and / or validate the existing ones, besides offering an overview of the pharmacogenetic profile...
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Tesis de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 19/12/2017