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Dihydropyrimidine Dehydrogenase (DPYD) and UPD Glucuronosyltransferase 1A1 (UGT1A1) Genotyping

3017866

Dihydropyrimidine Dehydrogenase (DPYD) and UPD Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 3017866

Method

Polymerase Chain Reaction (PCR)/Fluorescence Monitoring/Fragment Analysis

Predicts risk of dose-related toxicity to 5-FU therapy. May be useful in dosage planning for individuals who will receive high-dose irinotecan, have personal or family history of sensitivity to irinotecan, or have experienced neutropenia while receiving irinotecan.

For more information about individual DPYD testing, refer to the Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants Test Fact Sheet.

For more information about individual UGT1A1 testing, refer to the UGT1A1 Gene Analysis Test Fact Sheet.

Dihydropyrimidine dehydrogenase, an enzyme encoded by the DYPD gene, is responsible for metabolizing 5-fluorouracil (5-FU), a chemotherapeutic drug frequently used to treat many types of cancer, including colorectal adenocarcinomas. Germline variants in DPYD affect enzyme production, which may result in dose-related toxicity or in a reduction of treatment effectiveness. Similarly, variants in UGT1A1 can cause a deficiency in the enzymes involved in metabolizing the chemotherapeutic drug irinotecan and therefore increase the risk of drug toxicity.

Disease Overview

Genetics

Genes/Variants Tested

DPYD

1679T>G (DPYD*13, rs55886062)
1905+1G>A (DPYD*2A, rs3918290)
2846A>T (rs67376798)

UGT1A1

UGT1A1*36, (TA)5
UGT1A1*28, (TA)7
UGT1A1*37, (TA)8
UGT1A1*1, (TA)6

Inheritance

DPYD: autosomal codominant

UGT1A1: varies

Test Interpretation

Analytic Sensitivity/Specificity

DPYD: 99%

UGT1A1: 99%

Results

Gene	Result	Clinical Significance
DPYD	Positive: target variants of significance detected	Predicts decreased DPD enzymatic activity Associated with an increased risk for grade 3-4 5-FU toxicity
DPYD	Negative: 1/1 detected	Predicts normal metabolizer phenotype and average risk for 5-FU toxicity
UGT1A1	Positive: target variants of significance detected	Associated with an increased risk of irinotecan toxicity
UGT1A1	Negative: *1, (TA)6 detected	Associated with normal UGT1A1 enzyme levels and average risk of irinotecan toxicity

Limitations

Dihydropyrimidine Dehydrogenase (DPYD)

Only targeted variants in the DPYD gene will be detected.
Diagnostic errors may occur due to rare sequence variations.
Genetic and/or nongenetic factors not detected by this test may affect 5-FU drug metabolism and efficacy and the risk for toxicity.
Genotyping does not replace the need for therapeutic drug monitoring or clinical observation.
A negative result for the targeted DPYD variants does not rule out risk for 5-FU toxicity or predict degree of responsiveness to 5-FU.

UDP Glucuronosyltransferase 1A1 (UGT1A1)

Only targeted variations in the UGT1A1 gene will be detected.
Diagnostic errors can occur due to rare sequence variations.
The clinical significance of the rare *36, (TA)5 and *37, (TA)8 alleles in predicting irinotecan toxicity is not well established.
Genetic and nongenetic factors other than UGT1A1 may contribute to irinotecan toxicity and efficacy, and risk for bilirubin-related discontinuation of atazanavir.

References

Fluorouracil therapy and DPYD genotype

Dean L, Kane M. Fluorouracil therapy and DPYD genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al, eds. Medical Genetics Summaries. Bethesda, Maryland. Updated Jan 2021; accessed Aug 2024.

Irinotecan therapy and UGT1A1 genotype

Dean L. Irinotecan therapy and UGT1A1 genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al, eds. Medical Genetics Summaries. Bethesda, Maryland. Updated Apr 2018; accessed Aug 2024.

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