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Rare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report.

ABSTRACT: Variations in the activity, up to absolute deficiency, of the enzyme dihydropyrimidine dehydrogenase (DPD), result in the occurrence of adverse reactions to chemotherapy, and have been included among the pharmacogenetic factors underlying inter-individual variability in response to fluoropyrimidines. The study of single-nucleotide polymorphisms of the DPYD gene, which encodes the DPD enzyme, is one of the main parameters capable of predicting reduced enzymatic activity and the consequent influence on fluoropyrimidine treatment, in terms of reduction of both adverse reactions and therapeutic efficacy in disease control. In this paper, we describe a patient with metastatic breast cancer showing signs of increased toxicity following capecitabine therapy. The DPD enzyme activity analysis revealed a partial deficiency. The study of the most frequent polymorphisms of the DPYD gene suggested a wild-type genotype but indicated a novel variant c.1903A>G (p.Asn635Asp), not previously described, proximal to the splice donor site of exon 14. After excluding the potential pathogenic feature of the newly-identified variant, we performed cDNA sequencing of the entire DPYD coding sequence. This analysis identified the variants c.85T>C and c.496A>G, which were previously described as pivotal components of the haplotype associated with decreased enzyme activity and suggested that both variant alleles are related to DPD deficiency. The clinical case findings described in this study emphasize the importance of performing complete genetic analysis of the DPYD gene in order to identify rare and low frequency variants potentially responsible for toxic reactions to fluoropyrimidine treatment.

SUBMITTER: Palmirotta R

PROVIDER: S-EPMC6421267 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Rare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report.

Palmirotta Raffaele R Lovero Domenica D Delacour Hervé H Le Roy Audrey A Cremades Serge S Silvestris Franco F

Frontiers in oncology 20190311

Variations in the activity, up to absolute deficiency, of the enzyme dihydropyrimidine dehydrogenase (DPD), result in the occurrence of adverse reactions to chemotherapy, and have been included among the pharmacogenetic factors underlying inter-individual variability in response to fluoropyrimidines. The study of single-nucleotide polymorphisms of the <i>DPYD</i> gene, which encodes the DPD enzyme, is one of the main parameters capable of predicting reduced enzymatic activity and the consequent ...[more]

PMID: 30915274

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Project description:IntroductionIn April 2019, French authorities mandated dihydropyrimidine dehydrogenase (DPD) screening, specifically testing uracilemia, to mitigate the risk of toxicity associated with fluoropyrimidine-based chemotherapy. However, this subject is still of debate as there is no consensus on a standardized DPD deficiency screening test. We conducted a real-life retrospective study with the aim of assessing the impact of DPD screening on the occurrence of severe toxicity and exploring the potential benefits of complete genotyping using next-generation sequencing.MethodsAll adult patients consecutively treated with 5-fluorouracil (5-FU) or its oral prodrug at six cancer centers between March 2018 and February 2019 were considered for inclusion. Dihydropyrimidine dehydrogenase deficiency screening included gene encoding DPD (DPYD) genotyping using complete genome sequencing and DPD phenotyping (uracilemia or dihydrouracilemia/uracilemia ratio) or both tests. Associations between each DPD screening method and (i) severe (grade ≥3) early toxicity and (ii) fluoropyrimidine dose reduction in the second chemotherapy cycle were evaluated using multivariable logistic regression analysis. Furthermore, we assessed the concordance between DPD genotype and phenotype using Cohen's kappa.ResultsA total of 551 patients were included. Most patients were tested for DPD deficiency (86%) including DPYD genotyping only (6%), DPD phenotyping only (8%), or both (72%). Complete DPD deficiency was not detected in the study population. Severe early toxicity events were observed in 73 patients (13%), with two patients (0.30%) presenting grade 5 toxicity. Despite the numerically higher toxicity rate in untested patients, the occurrence of severe toxicity was not significantly associated with the DPD screening method (p = 0.69). Concordance between the DPD genotype and phenotype was weak (Cohen's kappa of 0.14).ConclusionDue to insufficient numbers, our study was not able to demonstrate any added value of DPYD genotyping using complete genome sequencing to prevent 5-FU toxicity. The optimal strategy for DPD screening before fluoropyrimidine-based chemotherapy requires further clinical evaluation.

Dataset Information

Rare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report.

Publications

Rare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report.

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