Gene‐Specific Variant Classifier (DPYD‐Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase

Shrestha, Shikshya; Zhang, Cheng; Jerde, Calvin R.; Nie, Qian; Li, Hu; Offer, Steven M.; Diasio, Robert B.

doi:10.1002/cpt.1020

Cited by 51 publications

(66 citation statements)

References 38 publications

(70 reference statements)

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“…An extensive search of genetic variants of DPYD associated with enzyme deficiency and poor-metabolizer status has been performed and several genotypes were identified [5, 8, 22]. In agreement with three meta-analyses [10, 23, 24], our study confirmed the well-known role of c.1905+1G>A and c.2846A>T in fluoropyrimidine-associated ADRs.…”

Section: Discussionsupporting

confidence: 87%

“…Despite the c.2194A allele seems to be relatively common, conflicting results have been reported concerning its influence on DPD activity and association with clinically-relevant ADRs. Some studies did not assign a role to c.2194G>A in the occurrence of fluoropyrimidine toxicity [32, 33] and in silico analysis demonstrated a normal enzyme activity [8]. A study found that c.2194G>A showed weak evidence for association with reduced DPD activity in African-American patients; c.2194GA patients displayed a 29% reduction in DPD activity compared to the wild-type, although the linkage with c.557A>G (p.Y186C) may have played a prominent role [34].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

Cinieri²,

Michelucci

et al. 2019

Pharmacogenomics J

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Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

Cinieri²,

Michelucci

et al. 2019

Pharmacogenomics J

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“…nl/shared/genes/DPYD. However, in order for these variants to be included in Table 1, sufficient evidence regarding the effect on enzyme function or the onset of toxicity must be investigated, possibly by using the DPYD-Varifier [19] or by phenotyping patients who carry a novel variant. An update of this guideline will be published when a renewed recommendation is given following newly published articles.…”

Section: Dpyd Variants Associated With Toxicitymentioning

confidence: 99%

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction of DPYD and fluoropyrimidines

et al. 2019

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Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.

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“…3 This discrepancy is unsurprising as genotyping DPYD has been repeatedly characterized as being highly specific but with a poor sensitivity, thus possibly underestimating the actual incidence of DPD deficiency. 31 Consequently, and despite the continuous efforts to better understand the impact of new deleterious variants in DPYD 32 or to develop genetic scores to customize 5-FU dose, 33 preemptive genotyping remains unrecognized by both the European Society for Medical Oncology 34 and the US National Comprehensive Cancer Network panel. 35 Patients with U > 150 ng/ml should be precluded for any fluoropyrimidine-based therapy.…”

Section: Discussionmentioning

confidence: 99%

A Simple and Rapid UPLC‐UV Method for Detecting DPD Deficiency in Patients With Cancer

Marin

Krache

Palmaro

et al. 2020

Clinical Translational Sci

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Detecting patients with dihydropyrimidine dehydrogenase (DPD) deficiency is becoming a major concern in clinical oncology. Monitoring physiologic plasma uracil and/or plasma uracil-to-dihydrouracil metabolic ratio is a common surrogate frequently used to determine DPD phenotype without direct measurement of the enzymatic activity. With respect to the increasing number of patients rquiring analysis, it is critical to develop simple, rapid, and affordable methods suitable for routine screening. We have developed and validated a simple and robust ultraperformance liquid chromatography-ultraviolet (UPLC-UV) method with shortened (i.e., 12 minutes) analytical run-times, compatible with the requirements of large-scale upfront screening. The method enables detection of uracil (U) over a range of 5-500 ng/ml (265 nm) and of dihydrouracil (UH2) over a range of 40-500 ng/ml (210 nm) in plasma with no chromatographic interference. When used as part of routine screening for DPD deficiency, this method was fully able to discriminate nondeficient patients (i.e., with U levels < 16 ng/ml) from deficient patients at risk of severe toxicity (i.e., U > 16 ng/ml). Results from 1 month of routine testing are presented and, although no complete deficits were detected, 10.7% of the screened patients presented DPD deficiency and would thus require s decresed dose. Overall, this new method, using a simple preanalytical solid-phase extraction procedure, and based on use of a standard UPLC apparatus, is both cost-and time-effective and can be easily implemented in any laboratory aiming to begin routine DPD testing. Fluoropyrimidine drugs (i.e., 5-FU, oral capecitabine) have been a mainstay to treat a wide range of solid tumors in adults. 5-FU is characterized by extensive liver metabolism leading to inactive compounds, depending on a unique catabolic step driven by dihydropyrimidine dehydrogenase (DPD). DPD is coded by the DPYD gene, known to be highly polymorphic, with marked changes in phenotypic status. Consequently, patients exhibit a wide range of DPD activities, leading to a high risk of severe/lethal toxicities in individuals with poor metabolizer (PM) phenotype. 1,2 DPD deficiency accounts for the vast majority of life-threatening toxicities in patients treated with 5-FU or oral capecitabine, as demonstrated by numerous clinical reports and meta-analyses in recent decades. 3 Upfront detection of DPD deficiency is thus critical to customize dosing and ensure optimal treatment without triggering potentially lethal

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Gene‐Specific Variant Classifier (DPYD‐Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase

Cited by 51 publications

References 38 publications

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction of DPYD and fluoropyrimidines

A Simple and Rapid UPLC‐UV Method for Detecting DPD Deficiency in Patients With Cancer

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Gene‐Specific Variant Classifier (DPYD‐Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase

Cited by 51 publications

References 38 publications

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction of DPYD and fluoropyrimidines

A Simple and Rapid UPLC‐UV Method for Detecting DPD Deficiency in Patients With Cancer

Contact Info

Product

Resources

About

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients