Test ID: DPYDG    
Dihydropyrimidine Dehydrogenase, DPYD Full Gene Sequencing, Varies

Identifying individuals at increased risk of toxicity when considering 5-fluorouracil (5-FU) and capecitabine chemotherapy treatment

For an individual with suspected dihydropyrimidine dehydrogenase (DPD) deficiency, this test may be useful in identifying variants associated with decreased or absent DPD enzyme activity

This is a pharmacogenomics test associated with 5-fluorouracil and capecitabine drug sensitivity. Biallelic variation in the DPYD gene is also associated with dihydropyrimidine dehydrogenase (DPD) deficiency.(1) Individuals who have variations identified in the DPYD may benefit from genetic consultation.

5-Fluorouracil (5-FU) and its orally administered prodrug, capecitabine, are fluoropyrimidine-based chemotherapeutic agents that are widely used for the treatment of colorectal cancer and other solid tumors.

The dihydropyrimidine dehydrogenase (DPYD) gene encodes the rate-limiting enzyme for fluoropyrimidine catabolism and eliminates over 80% of administered 5-FU. Dihydropyrimidine dehydrogenase (DPYD) activity is subject to wide variability, mainly due to genetic variation (table 1). This results in a broad range of enzymatic deficiency from partial (3%-5% of population) to complete loss (0.2% of population) of enzyme activity.(2,3) Patients who are deficient in DPYD are at an increased risk for side effects and toxicity when undergoing 5-FU treatment.(4) In addition, pathogenic homozygous or compound heterozygous variants within DPYD are associated with dihydropyrimidine dehydrogenase (DPD) deficiency. DPD deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation.

Table 1. Known Genetic Variations Associated with Fluoropyrimidine Treatment

*Other or novel variations, besides those listed here, may also impact fluoropyrimidine-related side effects and tumor response and will be reported if detected.

**Alleles that are categorized as having normal enzyme activity (eg, *4, *5, *6, *9A) will not be reported if detected because variants with normal enzyme activity are not expected to impact fluoropyrimidine-related side effects and tumor response.

The DPYD gene is located on chromosome 1 and contains 2 transcripts. The longer transcript (NM_000110.3) contains 23 exons, and the shorter transcript (NM_001160301.1) contains 6 exons, with exon 6 being unique to this transcript. All exons from the longer transcript (NM_000110.3) and exon-intron boundaries are assessed.

Genetic variations involved in the metabolic pathway of fluoropyrimidines have been shown to contribute to the differences in clinical outcomes including toxicity and tumor response.

An interpretive report will be provided.

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics recommendations as a guideline.(5) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.

Dihydropyrimidine dehydrogenase (DPYD) genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's DPYD status.

Rare genetic variants exist that could lead to false-negative or false-positive results. Other variants in the primer binding regions can affect the testing, and ultimately, the genotype assessment made.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Large deletions or rearrangements are not detected by this assay, and these may affect DPYD protein expression and their impact on fluoropyrimidine related side effects and tumor response.

Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of appropriate family members may be useful to determine pathogenicity of the alteration.

This test is not designed to provide specific dosing or drug selection recommendations and is to be used as an aid to clinical decision making only. Drug-label guidance should be used when dosing patients with medications regardless of the predicted phenotype.

1. Online Mendelian Inheritance in Man: Dihydropyrimidine dehydrogenase deficiency. #274270. Updated 4/18/2012. Available from http://omim.org/

2. Caudle KE, Thorn CF, Klein TE, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013;94(6):640-645

3. Morel A, Boisdron-Celle M, Fey L, et al: Clinical relevance of different dihyropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006 Nov;5(11):2895-2904

4. FDA Table of Pharmacogenomic Biomarkers in Drug Labeling. Available at: http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

5. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424

6. Offer SM, Fossum CC, Wegner NJ, et al: Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res 2014;74(9):2545-2554

• Informed Consent for Genetic Testing
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• Pharmacogenomic Associations Tables
• Informed Consent for Genetic Testing (Spanish)