Referred Tests
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Test ID: DPYDG
Dihydropyrimidine Dehydrogenase, DPYD Full Gene Sequencing, Varies
Useful For 
Suggests clinical disorders or settings where the test may be helpful
Identifying individuals at increased risk of toxicity when considering 5-fluorouracil and capecitabine chemotherapy treatment
May be useful in identifying variants associated with decreased or absent dihydropyrimidine dehydrogenase enzyme activity for an individual with this deficiency suspected
Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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
| Gene | cDNA numbering | Alternative name | Enzyme activity | Phenotype? |
| DPYD | No variations identified | *1 |
|
|
| c.1905+1G->A | *2A | No activity or significantly reduced activity | High risk for fluoropyrimidine toxicity | |
| c.1679T->G | *13 | |||
| c.1898delC | *3 | |||
| c.299_302delTCAT | *7 | |||
| c.1156G->T | *12 | |||
| c.2846A->T | rs67376798 | Reduced activity | Increased risk for fluoropyrimidine toxicity | |
| c.1129-5923C->G | rs75017182 | |||
| c.703C->T | *8 | Probable reduced function | Increased risk for fluoropyrimidine toxicity | |
| c.2983G->T | *10 | |||
| c.1003G->T | *11 | |||
| c.557A->G | rs115232898 | |||
| c.1601C->T | *4 | Normal activity** | Normal risk for fluoropyrimidine toxicity | |
| c.1627A->G | *5 | |||
| c.2194C->T | *6 | |||
| c.85T->C | *9A |
*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.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Interpretation Provides information to assist in interpretation of the test results
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.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
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.
Clinical Reference Recommendations for in-depth reading of a clinical nature
1. OMIM: 274270 Dihydropyrimidine dehydrogenase deficiency.. Johns Hopkins University; 1986. Updated April 18, 2012. Accessed December 4, 2020. Available from https://www.omim.org/entry/274270
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. U.S. Food and Drug Administration (FDA): Table of Pharmacogenomic Biomarkers in Drug Labeling. FDA; Updated June 2020, Accessed December 4, 2020. Available at: 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