medigraphic.com
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

2013, Number 2

<< Back Next >>

Rev Invest Clin 2013; 65 (2)

Analysis of genetic polymorphisms of Thiopurine S-methyltransferase (TPMT) in Mexican pediatric patients with cancer

Moreno-Guerrero SS, Ramírez-Pacheco A, Dorantes-Acosta EM, Medina-Sanson A

Language: Spanish
References: 32
Page: 156-164
PDF size: 208.37 Kb.


ABSTRACT

Background. Thiopurine S-Methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs, such as 6- mercaptopurine, 6-thioguanine and azathioprine, leading to their inactivation. Individuals who carry TPMT allele variants are more likely to experience life-threatening toxicity when these drugs are given at a standard dose. Wildtype phenotype TPMT*1 exhibits high level of catalytic activity, while all variants manifest with a decreased enzymatic activity. Ethnic-related differences in the distribution of TPMT variant alleles have been found. In Mexico, limited information is available; so far only two studies have been published and clear differences exist between them. Material and methods. Allelic variants and genotypes of the TPMT gene were determined in 240 Mexican children with leukemia and solid tumors using DNA extracted from peripheral blood. Polymorphisms G460A and A719G were identified by PCR-RFLP and G238C by the specific-allele PCR assay. The enzyme variants were detected by allelic discrimination. Results. Homozygous wild-type genotype TPMT*1/TPMT*1 was found in 173 patients (72.1%); 67 cases (27.9%) were heterozygous: 18 with genotype TPMT*1/TPMT*3B (7.5%), 17 TPMT*1/TPMT*3C (7.1%), 16 TPMT*1/TMPT*2 (6.7%), 14 TPMT*1/TPMT*3A (5.8%), and 2 (0.8%) were homozygous for two variants: TPMT*2/ TPMT*3B in both. The allele frequencies were TPMT*1 in 411 (85.62%), TPMT*3B in 20 (4.1%), TPMT*2 in 18 (3.75%), TPMT*3C in 17 (3.55%) and TPMT*3A in 14 (2.9%). Conclusions. A high frequency and diversity of variant TPMT genotypes was found in this series with predominance of the TPMT*3B allele.


REFERENCES

  1. Relling MV, Hancock ML, Boyett JM, Evans WE, et al. Prognostic importance of 6-Mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 1999; 93: 2817-23.

  2. McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000; 14: 567-72.

  3. McLeod HL, Coulthards S, Thomas AE, Richards SM, et al. Analysis of thiopurine methyltransferasa variant alleles in childhood acute lymphoblastic leukemia. British Journal Haematol 1999; 105: 696-700.

  4. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukemia. Lancet 1990; 336: 225-9.

  5. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. The American Society for Pharmacology and Experimental Therapeutics 2001; 29: 601-05.

  6. Seki T, Tanaka T, Nakamura Y. Genomic structure and multiple single-nucleotide polymorphisms (SNP’s) of the thiopurine S-methyltransferase (TPMT) gene. Journal Human Genetic 2000; 45: 299-302.

  7. Tai HL, Krynetski EY, Yates CR, Evans WE, et al. Thiopurine S-methyltransferase deficiency: Two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 1996; 58: 694-702.

  8. Coulthard SA, Howell C, Robson J, Hall AG. The relationship between Thiopurin Methyltransferase activity and genotype in blasts from patients with acute leukemia. Blood 1998; 92: 2856-62.

  9. Schaeffler E, Zanger UM, Eichelbaum M, et al. Highly Multiplexed Genotyping of Thiopurine S-Methiltransferase Variants Using MALDI-TOF Mass Spectrometry: Reliable Genotyping in Different Ethnic Groups. Clin Chem 2008; 54: 1637-47.

  10. Shufeng Z. Clinical Pharmacogenomics of Thiopurine S-methyltransferase. Current Clinical Pharmacology 2006; 1: 119-28.

  11. Stocco G, Cheok MH, Relling MV, Evans WE, et al. Genetic polymorphism of Inosine Triphosphate Pyrophosphatase is a determinant of Mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clinical Pharmacol Ther 2009; 85(2): 164-72.

  12. Krytnetski EY, Schutz JD, Gapin AJ, Evans WE, et al. A single mutation leading to loss of catalytic in human thiopurine s-methyltransferase. Proc Natl Acd Sci USA 1995; 92: 949-53.

  13. Schaeffeler E, Fischer C, Brockmeier D, Schwab M, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype- genotype correlation in a large population of German- Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004; 14: 407-17.

  14. Yates CR, Krynetski EY, Relling MV, Evans WE, et al. Molecular diagnosis of Thiopurine S-methyltranferase deficiency: Genetic basis for Azathioprine and Mercaptopurine intolerance. Annals of Internal Medicine 1997; 126: 608-14.

  15. Larovere LE, de Kremer RD, Lambooy LH, de Abreu RA. Genetic polymorphism of thiopurne S-methyltransferase in Argentina. Ann Clin Biochem 2003; 40: 388-93.

  16. Isaza C, Henao J, López AM, Cacabelos R. Allelic variants of the hiopurine methyltransferase (TPMT) gene in the Colombian population. Methos Find Exp Clin Pharmacol 2003; 25: 423-9.

  17. Lu HE, Sum MC, Hsuen SC, Chang JG, et al. Molecular analysis of the thiopurine S-methyltransferase alleles in Bolivians and Tibetans. Journal Clinical Pharmacology Therapy 2005; 30: 491-6.

  18. Boson WL, Romano-Silva MA, Correa H, Marco DL, et al. Thiopurine methyltransferase polymorphisms in a Brazilian population. The Pharmacogenomics Journal 2003; 3: 178-82.

  19. Reis M, Santoro A, Suarez-Kurtz G. Thiopurine methyltransferase phenotypes and genotypes in Brazilians. Pharmacogenetics 2003; 13: 371-3.

  20. Cao Q, Zhu Q, Shang Y, Gao M, Si J. Thiopurine Methyltransferase Gene Polymorphisms in Chinese patients with inflammatory Bowell Disease. Digestion 2009; 79: 58-63.

  21. Kapoor G, Maitra A, Somalata, Brahmachari. Application of SNaPshot for analysis of thiopurine methyltransferase. Indian J Med Res 2009; 129: 500-05.

  22. Taja-Chaveb L, Vidal-Millan S, Gutierrez O, Dueñas-Gonzalez A, et al. Thiopurine S-methyltranferase gene (TPMT) polymorphisms in a Mexican population of healthy individuals and leukemic patients. Med Oncology 2008; 25: 56-62.

  23. González del Ángel, Bermudes-López C, Alcántara-Ortigoza MA, Torres-Espindola L, et al. Thiopurine S-methyltransferase (TPMT) genetic polymorphisms in Mexican newborns. Journal Clinical Pharm Ther 2009; 34(6): 703-08.

  24. Corominas H, Doménech M, del Río E, Baiget M. Frecuencia y distribución de las variantes alélicas del gen de la tiopurina smetiltransferasa en distintos grupos étnicos españoles. Medical Clinical (Barcelona) 2006; 126(11): 410-2.

  25. McLeod HL, Pritchard SC, Githanga J, Collie-Duguid ESR, et al. Ethnic differences in thiopurine methyltransferase pharmacogenetics: evidence for allele specificity in Caucasian and Kenyan subjects. Pharmacogenetics 1999; 9: 773-6.

  26. Collie-Duguid ESR, Prichard SC, Powrie RH, McLeod HL, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999; 9: 37-42.

  27. Badell, Baiget ME, Fernández-Delgado R, Bure E, et al. Toxicidad en el tratamiento de mantenimiento del protocol LAL/ SHOP-2005. Estudio farmacogenético preliminary. Anales de pediatría 2007; 4: 442-3.

  28. Fajardo-Gutiérrez A, Juárez-Ocaña S, González-Miranda G, Mejía-Aranguré, et al. Incidence of cancer in children residing in ten jurisdictions of the Mexican Republic: importance of the Cancer registry (a population-based study). BioMed Central Cancer 2007; 7: 68.

  29. Juárez-Ocaña S, González Miranda G, Mejía Aranguré JM, Fajardo-Gutiérrez A. Frequency of cancer in children residing in Mexico City and treated in the hospitals of the Instituto Mexicano del Seguro Social (1996-2001). BioMed Cancer 2004; 4: 50.

  30. Medina-Sanson A, Martínez-Avalos A, Gallegos-Castorena S, et al. Pediatric oncology at hospital Infantil de Mexico: Fifty-Five Years of Accomplishment. Ped Hem Oncol 2002; 19: 383-7.

  31. Evans EW, Hon HY, Bomgaars L, et al. Preponderance of Thiopurine S-Methyl transferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptoprine or Azathioprine. J Clin Oncol 2001; 19: 2293-301.

  32. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med 2006; 57: 119-37.




2020     |     www.medigraphic.com