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HelpTest ID: DPYDG Dihydropyrimidine Dehydrogenase, DPYD Full Gene Sequencing, Varies
Useful For
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
Special Instructions
Method Name
Polymerase Chain Reaction (PCR) followed by DNA Sequence Analysis
Reporting Name
DPYD Full Gene SequencingSpecimen Type
VariesOrdering Guidance
Specimen Required
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send specimen in original tube.
Specimen Stability Information: Ambient (preferred) 9 days/Refrigerated 30 days
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Swab Collection Kit (T786)
Specimen Volume: 1 swab
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient 30 days
Specimen Type: Extracted DNA
Container/Tube: 2 mL screw top tube
Specimen Volume: 100 mcL (microliters)
Collection Instructions:
1. The preferred volume is 100 mcL at a concentration of 250 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated
Specimen Minimum Volume
Blood: 0.45 mL
Saliva: 1 swab
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Clinical Information
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 intellectual disabilities.
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
An interpretive report will be provided.
Interpretation
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.
Clinical Reference
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
Day(s) Performed
Varies
Report Available
5 to 10 daysTest Classification
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81232
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| DPYDG | DPYD Full Gene Sequencing | 94198-9 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 48263 | DPYD Predicted Toxicity Risk | 83009-1 |
| 48264 | Result Details | 82939-0 |
| 48268 | Interpretation | 69047-9 |
| 48266 | Method | 85069-3 |
| 48269 | Disclaimer | 62364-5 |
| 48270 | Reviewed by | 18771-6 |
| 92011 | Additional Information | 48767-8 |
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. If not ordering electronically, complete, print, and send a Therapeutics Test Request (T831) form with the specimen.
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