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


CONCLUSIONS
TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.
Departamento de Pediatría, Centro de Estudios Moleculares, Facultad de Medicina, Universidad de Chile, Antonio Varas 360, Santiago, Chile. mfarfan@med.uchile.cl.
Mauricio J
MJ
Farfan
Carolina
C
Salas
Cristina
C
Canales
Felipe
F
Silva
Milena
M
Villarroel
Katherine
K
Kopp
Juan P
JP
Torres
María E
ME
Santolaya
Jorge
J
Morales
D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage*; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase