Detection of Thiopurine S-Methyltransferase (TPMT) Polymorphisms TPMT*3A, TPMT*3B and TPMT*3C in Children with Acute Lymphoblastic Leukemia

Abstract

Background: Thiopurines are essential medications in Acute Lymphoblastic Leukemia (ALL) treatment protocols as anti-cancer agents since long time; however, their use might result in unexpected toxicities in ALL children due to the low thiopurine S-methyltransferase (TPMT) activity, a major enzyme involved in 6-mercaptopurine metabolism, which strongly correlates to the genetic polymorphism of the TPMT gene in those patients. Objective: To identify the most common TPMT polymorphisms in children with ALL and its frequencies. Methods: A cross sectional study enrolling eighty-one ALL children receiving mercaptopurine drug during their maintenance course of treatment according to UKALL-2011 protocol, were enrolled in this study. After DNA extraction from whole blood TPMT genetic polymorphisms were detected by allele-specific multiplex-PCR analysis. Results: A total of 51 children with allele frequencies of (62.96%) were homozygous for the wildtype allele TPMT*1, 30 children with allelic frequency of (37.03%) were heterozygous for one of the two mutant alleles (TPMT*3A or TPMT*3C) with allele frequencies of 29.62% and 7.4% respectively, while no result was found homozygous for two mutant alleles or TPMT*3B allele. Conclusions: This is the first study in Iraq to identify the genetic polymorphism of TPMT in a group of ALL children being treated for ALL. The study revealed the presence of TPMT*3A and TPMT*3C genetic polymorphisms among the study sample, no TPMT*3B was identified in the study sample. Keywords Acute Lymphoblastic Leukemia, 6-Mercaptopurine, Thiopurine S-methyltransferase, genetic polymorphisms. Introduction: Extraordinary advances in the treatment outcome of childhood Acute Lymphoblastic Leukemia (ALL) rank as one of the most successful stories in the history of oncology, with the current rate of approximately 80% of children being cured [1,2]. In spite of this success, there remains place for improvement, including the development of less toxic therapy [3, 4]. Thiopurine drugs, one of the medications that plays a major role in the maintenance phase of treatment of ALL, these drugs are purine analogue drugs which are metabolized inside the human body to form thioguanine nucleotide metabolites (TGNs), which have cytotoxic and immunosuppressive properties. However, these drugs like many cytotoxic agents have a relatively narrow therapeutic index. 6-Mercaptopurine (6-MP) is taken orally daily for a