| Interpretive Data: |
Background information for 5-Fluorouracil Sensitivity Through Genotyping (DPYD, TYMS and MTHFR) 8 Mutations
Characteristics: 5-fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs in the treatment of colorectal and other solid tumors. Adverse effects of 5-FU therapy, such as mucositis, neutropenia, nausea, diarrhea and neurological symptoms, occur in up to 15 percent of patients treated. Mutations in genes involved in 5-FU metabolism and response, including dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR), may be associated with 5-FU toxicity and/or altered response. 5-FU drug metabolism, efficacy, and risk for toxicity may be affected by genetic and non-genetic factors not detected by this assay. Genotyping does not replace the need for therapeutic drug or other clinical monitoring. For 5-FU Metabolism, refer to table below.
Prevalence: Population estimates for heterozygosity and homozygosity for DPYD alleles with impaired function are 3-5 percent and 0.1 percent, respectively. Heterozygosity for 1494 del TTAAAG (6 bp deletion) in TYMS occurs in 50 percent of Caucasians, 7 percent are homozygous. U.S. allele frequencies for MTHFR c.677C>T and c.1298A>C are 39 percent and 17 percent, respectively.
Cause: Deleterious mutations in genes involved with metabolism of and response to 5-FU including DPYD, TYMS and MTHFR.
Mutations Tested: Refer to table below.
Clinical Sensitivity & Specificity: Unknown.
Methodology: PCR and Detection Primer Extension.
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Only the targeted DPYD, TYMS and MTHFR mutations will be detected. Rare diagnostic errors may occur due to primer site mutation.
Counseling and informed consent are recommended for genetic testing. Consent forms are available online at www.aruplab.com.
Refer to Statement C under Testing Information at http://www.aruplab.com.
| 5-FU Metabolism
| | Gene name
| Protein name
| Normal protein function
| | DPYD
| DPD
| Inactivates approximately 80 percent of administered 5-FU
| | TYMS
| TS
| Primary drug target of 5-FU; complexes with an activated 5-FU metabolite resulting in suppression of DNA synthesis
| | MTHFR
| MTHFR
| Metabolizes folate to produce an activated co-factor needed for TS; impairment increases rate of activity of TS
|
| Mutations Tested
| | Gene
| Variant
| Variant Common Name
| Predicted Consequence
| | DPYD
| IVS14+1G>A
| *2
| Abolished DPD activity
| | | c.85T>C
| *9A
| Reduced DPD activity
| | | c.1679T>G
| *13
| Reduced DPD activity
| | | c.-1590T>C
| | Reduced DPD activity
| | | c.2846A>T
| | Reduced DPD activity
| | TYMS
| rs16430
| 1494 del TTAAAG
| Reduced TS expression
| | MTHFR
| c.677C>T
| C677T
| Reduced MTHFR activity
| | | c.1298A>C
| A1298C
| Reduced MTHFR activity
| | | | | |
|
| CPT Code(s): |
83891 Isolation; 83900 Multiplex amplification; 83901 x5 Additional amplification; 83914 x16 Extension; 83912 Interpretation and report - Additional CPT code modifiers may be required for procedures performed to test for oncologic or inherited disorders.
|
Cross References: |
5-FU (5-Fluorouracil Sensitivity (DYPD, TYMS and MTHFR) 8 Mutations)
, Thymidylate Synthase (5-Fluorouracil Sensitivity (DYPD, TYMS and MTHFR) 8 Mutations)
|
|