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

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.

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

“…It is indeed a rare variant being only infrequently reported in a Japanese population (one out of 269) [20], in Chinese leukemia children (one in 203) [65], but not found in Mexican paediatric patients with ALL (n = 70) [23]. The prevalence of ITPA-94AC/AA genotypes in Caucasian (15.1%) and Vietnamese (33.9%) children with ALL was in line with previous studies [37,54,58].…”

“…The effect of ITPA on relapse free survival (RFS) remains so far unclear. The prevalence of the ITPA-C94A transversion varies with ethnicity, ranging from 3.3% in Africans to 8.3% in Caucasians, 11-19% in Asians [54,56] and 3% in Chileans [58]. Accordingly, the first aim of this study was to compare the allele frequency distribution of the seven aforementioned loci in Caucasian and Vietnamese children with ALL.…”

Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects

“…They reported a higher incidence of 94C > A polymorphisms in the Asian population, with allele frequencies of 0.18, 0.16, and 0.11 in the Chinese, Malay, and Indian groups, respectively. Based on their genotype predictions, Rosalina et al identified patients more likely to develop hepatotoxicity and fever with 6-MP treatment.Mauricio et al[34] studied the prevalence of major genetic polymorphisms in the ITPA and TPMT genes for 6-MP metabolizing enzymes in Chilean children with ALL. The allele frequency of the 94C>A polymorphism was 3%.…”

The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment

“…Therefore, ITPA and NUDT15 may be better candidates for 6-MP pharmacogenomics in these populations [19], [27]. For instance, GWAS analysis reveals significant associations between NUDT15 415C>T and myelosuppression, especially in the aforementioned populations.…”