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

Farfan MJ, Salas C, Canales C, Silva F, Villarroel M, Kopp K, Torres JP, Santolaya ME, Morales J - BMC Cancer (2014)

Bottom Line: TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Pediatría, Centro de Estudios Moleculares, Facultad de Medicina, Universidad de Chile, Antonio Varas 360, Santiago, Chile. mfarfan@med.uchile.cl.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusion: TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.

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Related in: MedlinePlus

TPMT polymorphism and 6-MP dosage in Chilean children with ALL. Cumulative dosage (A) and daily dosage (B) of 6-MP between patients carrying a TPMT gene variant allele compared to patients carrying wild type alleles. The Mann–Whitney Rank Sum Test was used to compare 6-MP dosage between both groups. P values ≤0.05 were considered statistically significant.
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Figure 2: TPMT polymorphism and 6-MP dosage in Chilean children with ALL. Cumulative dosage (A) and daily dosage (B) of 6-MP between patients carrying a TPMT gene variant allele compared to patients carrying wild type alleles. The Mann–Whitney Rank Sum Test was used to compare 6-MP dosage between both groups. P values ≤0.05 were considered statistically significant.

Mentions: To associate the presence of a TPMT and ITPA polymorphism with 6-MP toxicity and dosage, we analyzed ALL patients who completed the maintenance phase. The analysis of the subgroup of 40 ALL patients, showed that 35/40 (88%) carried wild type alleles and 5/40 (12%) carried a TPMT variant allele. No statistical differences in the measured parameters between groups were seen (Table 2). We also determined the median cumulative dosage and median daily dosage of 6-MP in the same group of patients and found that ALL patient carrying a TPMT gene variant allele had a significantly lower median cumulative dosage and median daily dosage of 6-MP compared to patients carrying wild type alleles (Figure 2). No differences in 6-MP toxicity or dosage were associated with ITPA polymorphisms (data not shown).


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

Farfan MJ, Salas C, Canales C, Silva F, Villarroel M, Kopp K, Torres JP, Santolaya ME, Morales J - BMC Cancer (2014)

TPMT polymorphism and 6-MP dosage in Chilean children with ALL. Cumulative dosage (A) and daily dosage (B) of 6-MP between patients carrying a TPMT gene variant allele compared to patients carrying wild type alleles. The Mann–Whitney Rank Sum Test was used to compare 6-MP dosage between both groups. P values ≤0.05 were considered statistically significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4012712&req=5

Figure 2: TPMT polymorphism and 6-MP dosage in Chilean children with ALL. Cumulative dosage (A) and daily dosage (B) of 6-MP between patients carrying a TPMT gene variant allele compared to patients carrying wild type alleles. The Mann–Whitney Rank Sum Test was used to compare 6-MP dosage between both groups. P values ≤0.05 were considered statistically significant.
Mentions: To associate the presence of a TPMT and ITPA polymorphism with 6-MP toxicity and dosage, we analyzed ALL patients who completed the maintenance phase. The analysis of the subgroup of 40 ALL patients, showed that 35/40 (88%) carried wild type alleles and 5/40 (12%) carried a TPMT variant allele. No statistical differences in the measured parameters between groups were seen (Table 2). We also determined the median cumulative dosage and median daily dosage of 6-MP in the same group of patients and found that ALL patient carrying a TPMT gene variant allele had a significantly lower median cumulative dosage and median daily dosage of 6-MP compared to patients carrying wild type alleles (Figure 2). No differences in 6-MP toxicity or dosage were associated with ITPA polymorphisms (data not shown).

Bottom Line: TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Pediatría, Centro de Estudios Moleculares, Facultad de Medicina, Universidad de Chile, Antonio Varas 360, Santiago, Chile. mfarfan@med.uchile.cl.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusion: TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.

Show MeSH
Related in: MedlinePlus