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Test ID: GTPMT Thiopurine Methyltransferase (TPMT) Genotyping, Blood

Useful For

Predicting potential for toxicity to thiopurine drugs (6-mercaptopurine, 6-thioguanine, and azathioprine)

Reporting Name

TPMT Genotype, B

Specimen Type

Whole Blood EDTA


Specimen Required


Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.


Specimen Minimum Volume

0.35 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Clinical Information

The thiopurine drugs are purine antimetabolites that are useful in the treatment of acute lymphoblastic leukemia, autoimmune disorders (eg, Crohn disease, rheumatoid arthritis), and organ transplant recipients. The thiopurine drugs, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), and azathioprine (AZA) are prodrugs that require intracellular activation to 6-thioguanine nucleotides (6-TGN). This activation is catalyzed by multiple enzymes. The cytotoxic effects of thiopurine drugs are achieved mainly through incorporation of 6-TGNs into DNA and RNA. The pathway that leads to synthesis of active cytotoxic 6-TGNs is in competition with inactivation pathways catalyzed by thiopurine methyltransferase (TPMT). Evaluation of this pathway is important because the levels of 6-TGNs measured in red blood cells have been correlated with both thiopurine therapeutic efficacy and toxicity such as myelosuppression.

 

TPMT activity is inherited as a monogenic codominant trait and variable TPMT activity is associated with TPMT genetic variants. The distribution of TPMT activity in red blood cells is trimodal in Caucasian population, with approximately 0.3% of people having deficient (undetectable) TPMT activity, 11% low (intermediate) activity, and 89% normal TPMT activity. The allele for normal TPMT activity (wild-type) has been designated TPMT*1. Four TPMT alleles, comprised of a combination of 3 different single-nucleotide substitutions (SNPs), account for the majority of inactivating alleles in some ethnicities, including Caucasians: TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C. Additional less frequent TPMT alleles TPMT*4, TPMT*5, TPMT*8, and TPMT*12 also have been implicated as deficiency alleles. There is substantial evidence linking TPMT genotype to phenotypic variability and, therefore, genotyping tests have a high likelihood of being informative in these populations.

 

TPMT Allele

cDNA Nucleotide Change

Effect on Enzyme Metabolism

*1

None (wild type)

Extensive (normal) metabolizer

*2

c.238G->C

Nonfunctional, no activity

*3A

c.460G->A and c.719A->G

Nonfunctional, no activity

*3B

c.460G->A

Nonfunctional, no activity

*3C

c.719A->G

Nonfunctional, no activity

*4

c.626-1G->A

Nonfunctional, no activity

*5

c.146T->C

Nonfunctional, no activity

*8

c.644G->A

Reduced-function/decreased activity

*12

c.374C->T

Reduced-function/decreased activity

 

The US Food and Drug Administration, the Clinical Pharmacogenetics Implementation Consortium, and certain professional societies recommend consideration of TPMT genotype or TPMT erythrocyte testing prior to the initiation of therapy with thiopurine drugs. There is substantial evidence linking TPMT genotype to phenotypic variability. Dose adjustments based upon TPMT genotype have reduced thiopurine-induced adverse effects without compromising desired antitumor and immunosuppressive therapeutic effects in several clinical settings. Complementary clinical tests are available to measure TPMT enzymatic activity in erythrocytes. Genotyping is not impacted by other medications known to inhibit TPMT activity. This testing can be complimented by the TPMT erythrocyte phenotype testing if the clinician wants to check for lower TPMT enzyme activity, regardless of cause.

Reference Values

An interpretive report is provided.

Interpretation

An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating whether results are predictive of a poor, intermediate, or extensive metabolizer phenotype.

 

The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the TPMT Nomenclature Committee.(1)

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics 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. TPMT nomenclature committee. Available at www.imh.liu.se/tpmtalleles

2. Appell ML, Berg J, Duley J, et al: Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics 2013;23(4):242-248

3. Nguyen CM, Mendes MA, Ma JD: Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. PLoS Curr 2011;3:RRN1236

4. Relling MV, Gardner EE, Sandborn WJ, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-391

5. Weinshilboum R: Thiopurine pharmacogenetics clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos 2001 Apr;29(4 Pt 2):601-605

6. Zaza G, Cheok M, Krynetskaia N, et al: Thiopurine pathway. Pharmacogenet Genomics 2010 Sep;20(9):573-574

Day(s) and Time(s) Performed

Monday through Friday, 8 a.m.

Analytic Time

1 day (not reported on Saturday or Sunday)

Test 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 U.S. Food and Drug Administration.

CPT Code Information

81401-TPMT (thiopurine S-methyltransferase) (eg, drug metabolism), common variants (eg, *2, *3)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
GTPMT TPMT Genotype, B 41048-0

 

Result ID Test Result Name Result LOINC Value
36016 TPMT Genotype Result 63454-3
36017 TPMT Interpretation 69047-9
36018 Reviewed By No LOINC Needed

Method Name

Polymerase Chain Reaction (PCR) 5'-Nuclease End-Point Allelic Discrimination Analysis

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.

2. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

Neurology Specialty Testing Client Test Request (T732) http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)

Gastroenterology and Hepatology Test Request Form (T728) (http://www.mayomedicallaboratories.com/it-mmfiles/gastroenterology-and-hepatology-test-request.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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