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PREDICTION OF THIOPURINE TOXICITY – TPMT AND NUDT15 TESTING

Clinical Genetics Oncology


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.

CPIC Guidelines for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes:2018 Update.

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
TPMT TPMT*3A c.460G>A,
c.719A>G
p.Ala154Thr,
p. Tyr240Cys
rs1800460,
rs1142345
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.

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