Variants in the <i>Dihydropyrimidine Dehydrogenase, Methylenetetrahydrofolate Reductase</i> and <i>Thymidylate Synthase</i> Genes Predict Early Toxicity of 5-Fluorouracil in Colorectal Cancer Patients

Kristensen, MH; Pedersen, Palle; Melsen, GV; Ellehauge, J; Mejer, Johannes

doi:10.1177/147323001003800313

Cited by 48 publications

(42 citation statements)

References 60 publications

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“…Furthermore, a correlation between the DPYD*2A variant and reduced enzyme activity in peripheral blood mononuclear cells (PBMCs) was found in several ex vivo studies that confirmed decreased function of DPYD*2A [26,[28][29][30] and consequently an association was also found between DPYD*2A and reduction in fluoropyrimidine clearance in patients [31,32]. In numerous studies an association between DPYD*2A allele carriership and the increased risk of toxicity related to fluoropyrimidine treatment was confirmed [4,24,31,[33][34][35][36][37][38][39][40][41][42][43][44][45]. For example, in a meta-analysis by Terrazzino et al a strong correlation between the DPYD*2A allele and overall grade ≥3 toxicity was found (odds ratio 5.42, p < 0.001) [33].…”

Section: Previous Guidelines and Recommendationsmentioning

confidence: 83%

Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score

et al. 2015

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The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.

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Section: Previous Guidelines and Recommendationsmentioning

confidence: 83%

Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score

et al. 2015

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“…1,10 These polymorphisms have been previously observed in patients with low DPD enzymatic activity 20 and in some cases were associated to toxicity Grade 3 in the clinical setting. [21][22][23][24] The first aim of our study is to validate the specificity of three DPYD SNPs recommended by CPIC guidelines (i.e., DPYD-rs3918290, DPYD-rs55886062, and DPYD-rs67376798) in predicting the occurrence of severe toxicity events in a large set of oncological patients treated with FL in different clinical settings. 1 The second aim is to evaluate whether the additional testing of other investigational DPYD variants (DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYD-rs1801159, and DPYD-rs17376848) could increase the pharmacogenetic test sensitivity and is worthy to be integrated in the FL dosing guidelines.…”

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confidence: 99%

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Toffoli

Giodini

Buonadonna

et al. 2015

Intl Journal of Cancer

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Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYDrs1801159, DPYD-rs17376848) for association with Grade 3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade 3 toxicity after bootstrap validation and Bonferroni correction (p 5 0.003, p 5 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade 3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade 3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYDrs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade 3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.The identification of the genetic bases of inter-individual variability in terms of response or toxicity to pharmacological treatments is a key point in the field of personalized therapy. Specifically, in the oncological setting the high variability observed in the tumor response to treatment and in the severity of toxicity emphasizes the importance of improving the knowledge on the clinical validity of the pharmacogenetic tests.Fluoropyrimidines (FL) are listed among the drugs with pharmacogenetic warnings. 1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug...

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“…Detection of the genetic polymorphism is thought to be a useful method for the prediction of severe toxicity and treatment outcome. Although the detection of the DPYD gene SNP cannot predict all the severe toxicity, ~20% of all early 5-FU-related toxicities could potentially be avoided (1). The identification of the remaining 80% 5-FU toxicity must be reliant on the discovery and analysis of additional DPYD polymorphisms that can affect pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis

Leung

Chan

2015

Biomedical Reports

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Abstract. The aim of the present study was to evaluate the association and prediction of dihydropyrimidine dehydrogenase gene (DPYD) polymorphisms and the risk of 5-fluorouracil (5-FU) severe toxicity in cancer patients. A meta-analysis of the published literature was conducted to summarize evidence for DPYD gene polymorphisms associated with an increased risk of severe 5-FU toxicity in patients with cancer from an Asian population. Relevant literature was identified using the PubMed and Cochrane databases on April 11, 2014. Combined risk ratios and 95% confidence intervals (CIs) were calculated in a fixed-effects model. A total of 5 clinical studies were retrieved in the meta-analysis, including 764 cancer patients with DPYD gene polymorphisms who received 5-FU-based chemotherapy. Overall, DPYD gene polymorphisms were associated with the increased risk of 5-FU severe toxicity [risk ratio=2.54 (2.15-3.00); 95% CI, P=0.0001]. In conclusion, the present meta-analysis suggested that polymorphisms of several DPYD gene polymorphisms are associated with an increased risk of severe toxic response to 5-FU.

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Variants in the Dihydropyrimidine Dehydrogenase, Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes Predict Early Toxicity of 5-Fluorouracil in Colorectal Cancer Patients

Cited by 48 publications

References 60 publications

Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score

Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis

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