Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia.

Mauricio J Farfan,Katherine Kopp,Milena Villarroel,Jorge Morales,Cristina Canales,Juan P Torres,María E Santolaya,Felipe Silva,Carolina Salas

doi:10.1186/1471-2407-14-299

Mauricio J Farfan, Katherine Kopp + Show 7 more

Open Access

https://doi.org/10.1186/1471-2407-14-299

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Journal: BMC cancer	Publication Date: Apr 28, 2014
Citations: 59	License type: cc-by

Affiliation: Hospital Luis Calvo Mackenna, University of Chile

Abstract

BackgroundMercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); however, interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described. We determined the prevalence of the major genetic polymorphisms in 6-MP metabolizing enzymes in Chilean children with ALL.Methods103 Chilean pediatric patients with a confirmed diagnosis of ALL were enrolled. DNA was isolated from whole blood and genetic polymorphism in thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) coding genes were detected by polymorphism chain reaction-restriction fragment length (PCR-RFLP) assay.ResultsThe total frequency of variant TPMT alleles was 8%. TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively. For ITPA, the frequency of P32T allele was 3%. We did not observe any homozygous variant for TPMT and ITPA alleles. We also analyzed a subgroup of 40 patients who completed the maintenance phase of ALL treatment, and we found that patients carrying a TPMT gene variant allele required a significantly lower median cumulative dosage and median daily dosage of 6-MP than patients carrying wild type alleles.ConclusionTMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.

Highlights

Mercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described
Prevalence of thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genetic polymorphisms in ALL patients We enrolled 103 patients newly diagnosed with childhood ALL having a mean age of 8.7 years; 42/103 (41%) were male
We found no homozygous variant for TPMT and ITPA genes and no TPMT*2 and TPMT*3B alleles (Table 1)

Summary

Introduction

Mercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described. Mercaptopurine (6-MP) is a highly effective chemotherapeutic agent for the treatment of childhood acute lymphoblastic leukemia (ALL), and is extensively used in therapeutic protocols worldwide [1]. TPMT exhibits genetic polymorphism in all large ethnic groups, including Caucasians, Africans, African-Americans, and Asians and has been associated with high levels of 6-MP metabolites plasma level and toxicity [8]. One in 300 persons inherit two variant TPMT alleles and are TPMT deficient, and about 5%-10% are heterozygotes with intermediate enzyme activity, leading to severe and moderate to severe myelosuppression when patients are treated with conventional doses [6]. More than 20 SNPs for TPMT have been described, but alleles TPMT*2 (1800462), TPMT*3A (rs1800460), and TPMT*3C (rs1142345) comprise about 80-95% of all variant alleles described so far [1,2,3]

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Conclusion