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

• Published in: BMC cancer 2014-04, Vol.14 (1), p.299-299, Article 299
• Main Authors: Farfan, Mauricio J, Salas, Carolina, Canales, Cristina, Silva, Felipe, Villarroel, Milena, Kopp, Katherine, Torres, Juan P, Santolaya, María E, Morales, Jorge
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Adolescent; Alleles; Chemotherapy; Child; Child, Preschool; Confidence intervals; Deoxyribonucleic acid; DNA; DNA methylation; Drug dosages; Enzymes; Female; Genotype; Humans; Male; Mercaptopurine - administration & dosage; Metabolites; Methyltransferases - genetics; Patients; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Pyrophosphatases - genetics; Software; Studies; Toxicity
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-14-299

Mercaptopurine (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. 103 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. The 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. TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.