The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics

Abstract

Thiopurine methyltransferase catalyzes the S-methylation of azathioprine (AZA), 6-mercapto-purine (6-MP) and thioguanine, medications widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease and solid organ transplant rejection. TPMT activity exhibits a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity, including fatal myelosuppression, after receiving standard doses of thiopurine medications. The molecular basis for low TPMT activity has been elucidated, leading to the development of assays for the three signature mutations, which account for the majority of mutant alleles. TPMT genotype is correlated with erythrocyte and leukemia blast cell TPMT activity and associated with a risk of toxicity after thiopurine therapy. Recent studies defined target starting doses for mercaptopurine based on TPMT genotypes. This polymorphism is one of the best models for the translation of genomic information to guide patient therapeutics.

Thiopurine methyltransferase polymorphisms in a Brazilian population

“…7,8 TPMT is inherited as an autosomal codominant trait 9,10 and exhibits a genetic polymorphism with 1/300 individuals having complete deficiency and about 10% of Caucasians having intermediate activity because of heterozygosity. [11][12][13] The molecular basis for low TPMT activity has been elucidated with the identification of the wild-type (WT) allele TPMT*1 and three nonsynonymous single-nucleotide polymorphisms accounting for the majority of mutant alleles. [14][15][16][17] Patients with low or intermediate enzyme activity are at risk to develop severe hematopoietic toxicity after receiving standard doses of thiopurine medications.…”

Cancer pharmacogenetics

“…Intermediate-activity patients have a greater incidence of thiopurine toxicity, whereas TPMT-deficient patients have severe or fatal toxicity from mercaptopurine therapy. To date, at least 10 variations in the TPMT gene have been associated with low TPMT enzyme activity (McLeod and Siva, 2002). Three of these variants (TPMT*2, TPMT*3A and TPMT*3C) account for up to 95% of low TPMT activity phenotypes.…”

“…A significant variation in TPMT allele frequencies is seen among different world populations. TPMT*3A is the only variation found in Southwest Asians (1%), whereas all variant alleles in African populations are TPMT*3C (5.4 -7.6%) (McLeod and Siva, 2002). Pretreatment knowledge of a patient's TPMT genotype status is now being used in major centres for dose optimisation, in order to reduce prospectively the likelihood of adverse drug reactions in children with ALL.…”

Genomic medicine: a new frontier of medicine in the twenty first century

“…A simple assay to measure TPMT enzyme activity will allow the clinician to modify the drug dose in patients with low enzyme activity and thus minimize the risk of the fatal complication of myelosupression. The TPMT polymorphism is probably an excellent model for translational genomics in guiding the patient therapeutics or in other words supporting the concept of personalized medicine (McLeod and Siva 2002). The age of personalized medicine has begun.…”