Patients homozygous for DPYD c.1129-5923C&gt;G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines

Meulendijks, Didier; Henricks, Linda M.; Kuilenburg, André B. P.; Jacobs, Bart; Aliev, Abidin; Rozeman, Lisette; Meijer, Judith; Beijnen, Jos H.; Graaf, Hiltje de; Cats, Annemieke; Schellens, Jan H.M.

doi:10.1007/s00280-016-3137-0

Cited by 20 publications

(9 citation statements)

References 21 publications

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“…A moderate reduction in DPD activity was observed in heterozygous carriers of c.2846A>T and c.1129–5923C>G (30% and 35% reduced activity, respectively) . Two homozygous carriers of c.1129–5923C>G had 41% and 55% DPD activity compared to controls, consistent with a partial DPD deficiency . Homozygous expression in vitro resulted in dramatically reduced DPD activity (<25% of wildtype activity) for c.1905+1G>A and c.1679T>G, and in reduced DPD activity (39–59% of wildtype activity) for c.2846A>T .…”

Section: Drugs: Fluoropyrimidinesmentioning

confidence: 82%

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update

Amstutz

Henricks

Offer

et al. 2017

Clin Pharma and Therapeutics

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471

637

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The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5‐fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost‐effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC®) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/).

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Section: Drugs: Fluoropyrimidinesmentioning

confidence: 82%

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update

Amstutz

Henricks

Offer

et al. 2017

Clin Pharma and Therapeutics

Self Cite

471

637

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“…More recently, a collection of SNPs termed HapB3, which is composed of three intronic variants (rs56276561 (NM_000110.3:c.483+18G>A), rs6668296 (NM_000110.3:c.680+139G>A), and rs115349832 (NM_000110.3:c.959‐51T>C)) and one synonymous variant (rs56038477 (NM_000110.3:c.1236G>A; NP_000101.2:p.Glu412=)), has been suggested to also contribute to 5‐FU toxicity . Subsequently, an additional variant in linkage disequilibrium with HapB3 rs75017182 (NM_000110.3:c.1129‐5923C>G) was suggested to activate a splice donor site within intron 10 and promote alternative splicing to include a 44‐nucleotide cryptic exon . Despite the putative mechanistic explanation for the link between HapB3 and 5‐FU toxicity, the quantitative contribution of HapB3/rs75017182 to alternative splicing and DPD function has not been demonstrated.…”

mentioning

confidence: 99%

“…A recent meta‐analysis has provided evidence that HapB3/rs75017182 may increase the risk of 5‐FU toxicity . However, it should be noted that, while some clinical studies and case report series have indicated that HapB3/rs75017182 may be predictive of toxicity, additional studies have failed to establish statistically significant associations …”

mentioning

confidence: 99%

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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“…The frequency of heterozygous patients in Caucasian populations varies between 2.6% and 6.3% [42][43][44][45][46] . DPD activity is not completely absent in homozygous carriers; so it is expected that a 25% dose reduction for heterozygous carriers is convenient [34,47] .…”

Section: Dose Individualization Based On Specific Genotypementioning

confidence: 99%

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

Merloni¹,

Ranallo²,

Scortichini³

et al. 2019

CDR

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Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

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Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines

Abstract: The presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.

Cited by 20 publications

References 21 publications

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update

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

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

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