The low frequency of defective TPMT alleles in Turkish population: A study on pediatric patients with acute lymphoblastic leukemia

Abstract

6-Mercaptopurine (6MP) is an essential anticancer drug used in the treatment of childhood acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe toxicity or efficacy of 6MP. Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C, are responsible over the 80% of low or undetectable enzyme activity. The frequencies of these variants were investigated among 106 children with ALL in Turkish population. TPMT*3A and TPMT*3C were the only deficiency alleles detected in Turkish population with an allele frequency of 0.9% for both. While *3C allele frequency in Turkish population was found to be very similar to Asian and other Caucasian populations, *3A allele frequency was significantly (P < 0.05) lower. So far, studies showed that the genetic polymorphisms of other drug metabolizing enzymes like CYP2E1, CYP1A1, GSTM1/ T1 in Turkish population were similar to Caucasian populations. However, we found that the distribution of TPMT polymorphisms in Turkish population was significantly lower than those in other Caucasians like British, French, and Italian whereas the distributions of TPMT variants were found to be very similar to Kazak population which is also Caucasian in ethnic origin. In this study, the clinical histories of the patients in the sample population were also examined, retrospectively. The patients with heterozygous or homozygous mutant genotypes had developed severe neutropenia and infection during 6MP therapy. The study provides the first data on the frequency of common TPMT variants in the Turkish population, based on analysis of pediatric patients with ALL.

Thiopurine methyltransferase genotyping in Palestinian childhood acute lymphoblastic leukemia patients

“…TPMT*3A allele frequency is consistent with ethnically related Israeli Arab subpopulations (0.79%) [16]. The frequency of TPMT*3A allele is also similar in Jordanian population (0.59) [17], Turkish population (0.9%) [18], and Iranian population (0.87%) [19]. It is lower than that reported for several Caucasian, African descendants and South American [17].…”

Association Between Combined Presence of Hepatitis C Virus and Polymorphisms in Different Genes With Toxicities of Methotrexate and 6‐Mercaptopurine in Children With Acute Lymphoblastic Leukemia

“…TPMT*3A allele frequency was consistent with the screened Palestinian population (0.89%), and ethnically related Israeli Arab subpopulations (0.79%) . The frequency of TPMT*3A allele was also similar to Jordanian population (0.59%), Turkish population (0.9%), and Iranian population (0.87%) . It was lower than the frequency reported for several Caucasian, African descendants, and South Americans …”

Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

“…The TPMT*3A allele is mutated at both nucleotides G460A and A719G whereas TPMT*3B and TPMT*3C only have the G460A or A719G mutation, respectively [45][46][47]. The prevalence of the TPMT*3A mutation ranges from 0.9 to 5.7% in Caucasians but is usually not found in Asians [48][49][50] whereas the prevalence of the TPMT*3C mutation varies between 0.6 and 3% in Asians vs. 0.3 and 1.6% in Caucasians [48,[50][51][52].…”