| Interpretive Data: |
Background information for 5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 7 Mutations:
Characteristics: 5-FU is the most frequently used chemotherapeutic drug for the treatment of many types of cancer, particularly colorectal adenocarcinoma. Grade III-IV drug toxicity attributed to 5-FU occurs in approximately 16 percent of patients, and may include hematologic, gastrointestinal, and dermatologic complications. In some cases, this toxicity can cause death. When 5-FU is metabolized in the body, approximately 80 percent is catabolized by the dihydropyrimidine dehydrogenase (DPYD) enzyme. The remaining drug is further metabolized into an active form that inhibits the synthesis of both DNA and RNA by either competitive inhibition of the thymidylate synthase (TYMS) enzyme or by direct incorporation of cytotoxic metabolites into nucleic acids. Mutations in the DPYD gene can lead to reduced 5-FU catabolism, resulting in the aforementioned toxicity complications. The TYMS enzyme is the primary target of 5-FU. Mutations in the 5'-promoter enhancer region (5'-TSER) and the 3'-untranslated region (3'-UTR) of the TYMS gene have been correlated to TYMS expression levels, responsiveness to 5-FU therapy, and clinical outcome.
Clinical Sensitivity and Specificity: Unknown
Methodology: DPYD genotypes are determined by multiplex PCR, single nucleotide extension (SNE), and fragment analysis. TYMS genotypes are determined by PCR, restriction digest, and fragment analysis.
Analytical Sensitivity and Specificity: 99 percent
Limitations: Only the targeted TYMS and DPYD mutations will be detected by this panel. Rare diagnostic errors may occur due to primer site mutations. 5-FU drug metabolism, efficacy and risk for toxicity may be affected by genetic and non-genetic factors that are not evaluated by this test. Genotyping does not replace the need for therapeutic drug monitoring or clinical observation.
Variants Tested:
Counseling and informed consent are recommended for genetic testing. Consent forms are available online at www.aruplab.com.
See Compliance Statement C: www.aruplab.com/CS
| Table 1. DPYD mutations: nomenclature, allele frequency, and predicted consequences
| | DPYD mutations
| Alternative name
| Allele frequency in
indicated population
| Predicted consequence
in patients receiving 5-FU
| | c.-1590 T>C
| N/A
| 0.007 - French Caucasians
| Decreased DPYD activity;
Increased toxicity risk
| | c.85 T>C
| DPYD*9A
| 0.185 - French Caucasians
| Decreased DPYD activity;
Increased toxicity risk
| | c.1679 T>G
| DPYD*13
| 0.001 - French Caucasians
| Decreased DPYD activity;
Increased toxicity risk
| | c.1905+1 G>A
| IVS14+1 G>A; DPYD*2A
| Absent - Japanese, Korean, African American
0.0047 - 0.022-Dutch, German, French, Turkish, Finnish
| Abolished DPYD activity;
Greatly increased toxicity risk;
Increased risk of toxicity-related death
| | c.2846 A>T
| N/A
| 0.01 - French Caucasians
| Decreased DPYD activity;
Increased toxicity risk
|
| Table 2. TYMS mutations, allele frequency, and predicted consequences
| | TYMS mutations
| Allele
| Allele frequency in
indicated population
| Predicted consequence in
patients receiving 5-FU
| 3'-UTR:
6 bp deletion (TTAAAG)
| INSERTION
| 0.705 - Caucasian
| Increased TYMS expression;
Decreased 5-FU responsiveness;
Decreased risk of toxicity
| 3'-UTR:
6 bp deletion (TTAAAG)
| DELETION
| 0.295 - Caucasian
| Decreased TYMS expression;
Increased 5-FU responsiveness;
Increased risk of toxicity
| 5'-TSER:
28bp VNTR (2R; 3R)
G>C SNP in 2nd repeat of 3R allele (3RC)
| 2R
| 0.41-0.48 - Caucasian, Hispanic, African-American
0.19 - Singapore, Chinese
0.175 - Japanese
| 2R/3RG:
Increased TYMS expression;
Decreased 5-FU responsiveness;
Poor prognosis
2R/2R or 2R/3RC:
Decreased TYMS expression;
Increased 5-FU responsiveness;
Increased risk of toxicity
| 5'-TSER:
28bp VNTR (2R; 3R)
G>C SNP in 2nd repeat of 3R allele (3RC)
| 3RG
| 0.26-0.37 - Caucasian, Hispanic, African-American
0.51 - Singapore, Chinese
0.427 - Japanese
| 3RG/3RG, 3RG/3RC or 2R/3RG :
Increased TYMS expression;
Decreased 5-FU responsiveness;
Poor prognosis
| 5'-TSER:
28bp VNTR (2R; 3R)
G>C SNP in 2nd repeat of 3R allele (3RC)
| 3RG
| 0.26-0.37 - Caucasian, Hispanic, African-American
0.51 - Singapore, Chinese
0.427 - Japanese
| Decreased TYMS expression;
Increased 5-FU responsiveness;
Increased risk of toxicity
| 5'-TSER:
28bp VNTR (2R; 3R)
G>C SNP in 2nd repeat of 3R allele (3RC)
| 3RC
| 0.15-0.33 - Caucasian, Hispanic, African-American
0.30 - Singapore, Chinese
0.399 - Japanese
| 3RG/3RC:
Increased TYMS expression;
Decreased 5-FU responsiveness;
Poor prognosis
3RC/3RC or 2R/3RC:
Decreased TYMS expression;
Increased 5-FU responsiveness;
Increased risk of toxicity
|
|
| CPT Code(s): |
81400, 81401,81479
|
Cross References: |
5-FU Toxicity and Chemotherapeutic Response, 7 Mutations, DPYD and TYMS Genotyping, 7 Mutations, TYMS and DPYD Genotyping, 7 Mutations |
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