What conditions are associated with the DPYD (Dihydropyrimidine Dehydrogenase) gene variant c.2846A>T?

From the Guidelines

Patients with the DPYD gene variant c.2846A>T are at increased risk of severe fluoropyrimidine-associated toxicity, and dose reduction of fluoropyrimidines is recommended to minimize this risk. The DPYD gene variant c.2846A>T is associated with dihydropyrimidine dehydrogenase (DPD) deficiency, which can lead to severe toxicity when patients are treated with fluoropyrimidine drugs like 5-fluorouracil (5-FU) and capecitabine 1. This variant is one of several clinically significant DPYD variants that should be considered when assessing the risk of fluoropyrimidine toxicity.

Key Points to Consider

• The DPYD gene variant c.2846A>T is associated with reduced DPD enzyme activity, which impairs the ability to metabolize fluoropyrimidine drugs 1.
• Patients with this variant are at increased risk of severe adverse effects, including diarrhea, mucositis, neutropenia, and potentially life-threatening toxicity 1.
• Dose reduction of fluoropyrimidines is recommended for patients carrying the DPYD:c.2846A>T variant, typically a 25-50% reduction of the standard dose initially, with subsequent dose adjustments based on tolerance 1.
• The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines provide dosing recommendations for 5-FU and 5-FU prodrug-based regimens based on DPYD genotype, including reduced starting doses for intermediate metabolizers and avoidance of fluoropyrimidines for poor metabolizers 1.

Clinical Implications

The presence of the DPYD gene variant c.2846A>T has significant implications for the clinical management of patients receiving fluoropyrimidine therapy. Dose reduction of fluoropyrimidines is crucial to minimize the risk of severe toxicity in patients with this variant. Additionally, uridine triacetate, an orally administered pyrimidine analog, is available for the emergency treatment of severe or life-threatening toxicity within 96 hours of fluoropyrimidine administration 1.

Recommendations

• Patients with the DPYD gene variant c.2846A>T should receive dose-reduced fluoropyrimidine therapy to minimize the risk of severe toxicity.
• The CPIC Guidelines should be consulted for specific dosing recommendations based on DPYD genotype.
• Uridine triacetate should be considered for emergency treatment of severe or life-threatening toxicity in patients with this variant.

From the Research

Conditions Associated with the DPYD Gene Variant c.2846A>T

The DPYD gene variant c.2846A>T has been associated with several conditions, including:

• Increased risk of treatment-related mortality in patients receiving fluoropyrimidine chemotherapy 2
• Grade 3-4 toxicity during fluoropyrimidine chemotherapy 3
• Severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine) 2, 3, 4, 5
• Dihydropyrimidine dehydrogenase (DPD) deficiency, an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents 2, 4
• Fluoropyrimidine-induced severe toxicity, which can be reduced by prospective DPYD genotyping 4

DPYD Genotyping and Dose Individualization

DPYD genotyping can be used to identify patients with the c.2846A>T variant, who are at increased risk of severe toxicity when treated with fluoropyrimidines. Studies have shown that:

• Prospective DPYD genotyping can reduce the risk of fluoropyrimidine-induced severe toxicity 4
• DPYD genotype-guided dose individualization can improve patient safety of fluoropyrimidine therapy 5
• Pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers can normalize 5-FU exposure and improve patient safety 5

Detection of the c.2846A>T Variant

The c.2846A>T variant can be detected using various methods, including:

• Multiplex allele-specific polymerase chain reaction (AS-PCR) assay, followed by capillary electrophoresis 6
• Sanger sequencing 6