Novel Deleterious Dihydropyrimidine Dehydrogenase Variants May Contribute to 5‐Fluorouracil Sensitivity in an East African Population

Elraiyah, Tarig; Jerde, Calvin R.; Shrestha, Shikshya; Wu, Rentian; Nie, Qian; Giama, Nasra H.; Sarangi, Vivekananda; Roberts, Lewis R.; Offer, Steven M.; Diasio, Robert B.

doi:10.1002/cpt.531

Cited by 32 publications

(39 citation statements)

References 29 publications

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“…Participants were excluded from participation if they were previously treated with chemotherapy. To align with the high prevalence of rs7501782 in European populations, participation in the present study was restricted to individuals that self‐declared race as “white.” Ethnicity, defined as Hispanic or non‐Hispanic in the Biobank, was not considered in the selection process. DNA aliquots were prepared by the Mayo Clinic Biospecimens Acquisition and Processing (BAP) shared resource.…”

Section: Methodsmentioning

confidence: 99%

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Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity

Nie

Shrestha

Tapper

et al. 2017

Clin Pharma and Therapeutics

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Dihydropyrimidine dehydrogenase (DPD; DPYD gene) variants have emerged as reliable predictors of adverse toxicity to the chemotherapy agent 5-fluorouracil (5-FU). The intronic DPYD variant rs75017182 has been recently suggested to promote alternative splicing of DPYD. However, both the extent of alternative splicing and the true contribution of rs75017182 to DPD function remain unclear. In the present study we quantified alternative splicing and DPD enzyme activity in rs75017182 carriers utilizing healthy volunteer specimens from the Mayo Clinic Biobank. Although the alternatively spliced transcript was uniquely detected in rs75017182 carriers, canonically spliced DPYD levels were only reduced by 30% (p=2.8×10−6) relative to controls. Similarly, DPD enzyme function was reduced by 35% (p=0.025). Carriers of the well-studied toxicity-associated variant rs67376798 displayed similar reductions in DPD activity (31% reduction). The modest effects on splicing and function suggest that rs75017182 may have clinical utility as a predictor of 5-FU toxicity similar to rs67376798.

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Section: Methodsmentioning

confidence: 99%

“…Reactions were terminated using cold 100% ethanol. Conversion of [6‐C 14 ]‐5‐FU to [6‐C 14 ]‐5‐dihydrofluorouracil ([6‐C 14 ]‐5‐DHFU) was assessed using high‐performance liquid chromatography (HPLC) as described . Rate of conversion was calculated as pmol 5‐FU min ‐1 mg ‐1 of total input protein as described …”

Section: Methodsmentioning

confidence: 99%

Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity

Nie

Shrestha

Tapper

et al. 2017

Clin Pharma and Therapeutics

Self Cite

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“…For example, in the Caucasian population,~3-5% has a partial DPD enzyme deficiency and 0.1-0.2% has a complete DPD enzyme deficiency. On the other hand,~8% of the African American population has a partial DPD enzyme deficiency [15,16].…”

Section: Gene: Dihydropyrimidine Dehydrogenase (Dpyd)mentioning

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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“…The primary goal of the present study was to develop a highly accurate in silico classifier to predict the functional impact of DPYD variants on DPD activity. To accomplish this, we measured the in vitro enzyme activity of 69 DPYD variants, which was combined with previous data from 87 variants . The developed multiparameter gene‐specific classifier, which we named DPYD‐Varifier ( DPYD ‐specific variant classifier) showed improved accuracy over existing in silico tools.…”

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confidence: 99%

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

Shrestha

Zhang

Jerde

et al. 2018

Clin Pharma and Therapeutics

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Deleterious variants in dihydropyrimidine dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. The developed model showed 85% accuracy and outperformed other in silico prediction tools. An examination of feature importance within the model provided additional insight into functional aspects of the DPD protein relevant to 5-FU toxicity. In the absence of clinical data for unstudied variants, prediction tools like DPYD-Varifier have great potential to individualize medicine and improve the clinical decision-making process.

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Novel Deleterious Dihydropyrimidine Dehydrogenase Variants May Contribute to 5‐Fluorouracil Sensitivity in an East African Population

Cited by 32 publications

References 29 publications

Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity

Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity

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

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

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