GENETIC TESTING OF THE TPMT AND NUDT15 GENES TO PREDICT TOXICITY IN PATIENTS TREATED WITH THIOPURINES
Thiopurines are used as anticancer agents and as immunosuppressants in inflammatory bowel disease, rheumatoid arthritis and other autoimmune conditions. Three thiopurines are used clinically: azathioprine (a prodrug for mercaptopurine), mercaptopurine, and thioguanine.
Thiopurine methyltransferase (TPMT) catabolizes thiopurines. Single nucleotide polymorphisms (SNPs) in the TPMT gene can produce unstable TPMT proteins with enhanced TPMT protein degradation resulting in low activity phenotypes. Similarly, loss of function alleles in the NUDT15 gene can reduce degradation of active thiopurine metabolites. Starting doses of thiopurines should be adjusted for patients in whom these SNPs are identified to prevent toxicity, in particular myelosuppression.
Three TPMT SNPs account for over 90% of low activity phenotypes and are the most common inactivating alleles in Europeans and Africans. NUDT15 risk alleles explain the majority of thiopurine-related myelosuppression in Asian populations and are also common in the Hispanic population.
Testing for the following variants is performed in the laboratory:
|Gene||Allele||Nucleotide change||Protein change||rsID||Genomic coordinates (GRCh38)|
|TPMT||TPMT*2||c.238 G>C||p.Ala80Pro||rs1800462||Chr 6: g.18143724 C>G|
|Chr 6: g.18138997C>T,
Chr 6: g.18130687 T>C
|TPMT||TPMT*3B||c.460G>A||p.Ala154Thr||rs1800460||Chr 6: g.18138997C>T|
|TPMT||TPMT*3C||c.719A>G||p. Tyr240Cys||rs1142345||Chr 6: g.18130687 T>C|
|NUDT15||NUDT15*3||c.415C>T||p.Arg139Cys||rs116855232||Chr 13: g.48045719 C>T|
Variant alleles are interpreted and a clinical report issued.
Complementary phenotyping can be a helpful adjunct to genotyping, especially when more than one heterozygous variant is identified.
The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.