Tumor Biology

, Volume 36, Issue 8, pp 6341–6348 | Cite as

N-Acetyltransferase 2 (NAT2) polymorphism as a risk modifier of susceptibility to pediatric acute lymphoblastic leukemia

  • Azza M. Kamel
  • Gamal T. A. Ebid
  • Heba S. Moussa
Research Article


N-Acetyltransferases (NAT) have been known to modify the risk to a variety of solid tumors. However, the role of NAT2 polymorphism in risk susceptibility to childhood acute lymphoblastic leukemia (ALL) is still not well known. We performed a case-control study to determine if the common NAT2 polymorphisms play a role in altering susceptibility to pediatric ALL. DNA of 92 pediatric ALL patients and 312 healthy controls was analyzed for the NAT2 polymorphisms using the PCR-RFLP method. The wild-type NAT2*4 was encountered in 8.6 % of patients versus 11.8 % of controls (P = 0.23). The rapid acetylators NAT2*12 803A>G, AG, GG, and AG/GG were overrepresented in controls (P = 0.0001; odds ratio (OR) 0.22, 0.19, and 0.21 respectively). NAT2*5D 341T>C and NAT2*11A 481C>T were of comparable frequencies. For their combination, NAT2*5A, a slow acetylator, both TCTT and CCCT were overrepresented in patients (P < 0.001; OR 15.8 and 17.9 respectively). NAT2*5B (803A>G, 341T>C, 481C>T) was overrepresented in controls (P < 0.001; OR 0.12). Apparently, 803A>G ameliorated the combined effect of 341T>C and 481C>T. A similar effect was obtained with NAT2*5C (341T>A, 803A>G) (P < 0.0001; OR 0.11). For slow acetylator NAT2*7A 857G>A, GA and GA/AA were overrepresented in patients (P = 0.009 and 0.01; OR 2.74 and 2.72 respectively). NAT2*13 282C>T, NAT2*6B 590G>A, and NAT2*14A 191G>A were of comparable frequencies. NAT2 282C>A in combination with NAT2 857G>A (NAT2*7B) showed a synergistic effect in patients versus controls (P < 0.0001; OR 3.51). In conclusion, NAT2 gene polymorphism(s) with slow acetylator phenotype is generally associated with the risk of development of ALL in children.


ALL NAT2 Risk susceptibility Single nucleotide polymorphism 


Conflicts of interest



  1. 1.
    Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381:1943–55. doi: 10.1016/S0140-6736(12)62187-4.CrossRefPubMedGoogle Scholar
  2. 2.
    Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact. 2012;196:59–67. doi: 10.1016/j.cbi.2012.01.007.CrossRefPubMedGoogle Scholar
  3. 3.
    Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML, et al. Common gene polymorphism in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiol Biomarkers Prev. 2004;13:787–94.PubMedGoogle Scholar
  4. 4.
    Kiss I, Sándor J, Pajkos G, Bogner B, Hegedüs G, Ember I. Colorectal cancer risk in relation to genetic polymorphism of cytochrome P450 1A1, 2E1, and glutathione-S-transferase M1 enzymes. Anticancer Res. 2000;20:519–22.PubMedGoogle Scholar
  5. 5.
    Rebbeck T. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1997;6:733–43.PubMedGoogle Scholar
  6. 6.
    Shields P, Harris C. Cancer risk and low-penetrance susceptibility genes in gene–environment interactions. J Clin Oncol. 2000;18:2309–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev. 2000;9:29–42.PubMedGoogle Scholar
  8. 8.
    Hein DW, Rustan TD, Ferguson RJ, Doll MA, Gray K. Metabolic activation of aromatic and heterocyclic N-hydroxyarylamines by wild-type and mutant recombinant human NAT1 and NAT2 acetyltransferases. Arch Toxicol. 1994;68:129–33.CrossRefPubMedGoogle Scholar
  9. 9.
    Grant DM, Hughes NC, Janezic SA, Goodfellow GH, Chen HJ, Gaedigk A, et al. Human acetyltransferase polymorphisms. Mutat Res. 1997;376:61–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Cascorbi I, Roots I. Pitfalls in N-acetyltransferase 2 genotyping. Pharmacogenetics. 1999;9:123–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Zheng W, Deitz AC, Campbell DR, Wen WQ, Cerhan JR, Sellers TA, et al. N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1999;8:233–9.PubMedGoogle Scholar
  12. 12.
    Probst-Hensch NM, Haile RW, Li DS, Sakamoto GT, Louie AD, Lin BK, et al. Lack of association between the polyadenylation polymorphism in the NAT1 (acetyltransferase 1) gene and colorectal adenomas. Carcinogenesis. 1996;17:2125–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Doll MA, Jiang W, Deitz AC, Rustan TD, Hein DW. Identification of a novel allele at the human NAT1 acetyltransferase locus. Biochem Biophys Res Commun. 1997;233:584–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Hengstler JG, Arand M, Herrero ME, Oesch F. Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. Recent Results Cancer Res. 1998;154:47–85.CrossRefPubMedGoogle Scholar
  15. 15.
    Zheng Y, Li Y, Teng Y, Zhang Z, Cao X. Association of NAT2 phenotype with risk of head and neck carcinoma: a meta-analysis. Oncol Lett. 2012;3:429–34.PubMedGoogle Scholar
  16. 16.
    de Lima Junior MM, Reis LO, Guilhen AC, Granja F, de Lima Oliveira MN, Ferreira U, et al. N-acetyltransferase-2 gene polymorphisms and prostate cancer susceptibility in Latin American patients. Med Oncol. 2012;29:2889–94. doi: 10.1007/s12032-012-0157-4.CrossRefPubMedGoogle Scholar
  17. 17.
    Cox DG, Dostal L, Hunter DJ, Le Marchand L, Hoover R, Ziegler RG, et al. N-acetyltransferase 2 polymorphisms, tobacco smoking, and breast cancer risk in the breast and prostate cancer cohort consortium. Breast and Prostate Cancer Cohort Consortium. Am J Epidemiol. 2011;174:1316–22. doi: 10.1093/aje/kwr257.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Barbieri RB, Bufalo NE, Secolin R, Silva AC, Assumpção LV, Maciel RM, et al. Evidence that polymorphisms in detoxification genes modulate the susceptibility for sporadic medullary thyroid carcinoma. Eur J Endocrinol. 2012;166:241–5. doi: 10.1530/EJE-11-0843.CrossRefPubMedGoogle Scholar
  19. 19.
    Ying XJ, Dong P, Shen B, Wang J, Wang S, Wang G. Possible association of NAT2 polymorphism with laryngeal cancer risk: an evidence-based meta-analysis. J Cancer Res Clin Oncol. 2011;137:1661–7. doi: 10.1007/s00432-011-1045-6.CrossRefPubMedGoogle Scholar
  20. 20.
    Hou YY, Ou HL, Chu ST, Wu PC, Lu PJ, Chi CC, et al. NAT2 slow acetylation haplotypes are associated with the increased risk of betel quid-related oral and pharyngeal squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112:484–92. doi: 10.1016/j.tripleo.2011.03.036.CrossRefPubMedGoogle Scholar
  21. 21.
    Goode EL, White KL, Vierkant RA, Phelan CM, Cunningham JM, Schildkraut JM, et al. Xenobiotic-metabolizing gene polymorphisms and ovarian cancer risk. Mol Carcinog. 2011;50:397–402. doi: 10.1002/mc.20714.CrossRefPubMedGoogle Scholar
  22. 22.
    da Silva TD, Felipe AV, de Lima JM, Oshima CT, Forones NM. N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer. World J Gastroenterol. 2011;17:760–5. doi: 10.3748/wjg.v17.i6.760.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cui D, Wang Z, Zhao E, Ma J, Lu W. NAT2 polymorphism and lung cancer risk: a meta-analysis. Lung Cancer. 2011;73:153–7. doi: 10.1016/j.lungcan.2010.12.012.CrossRefPubMedGoogle Scholar
  24. 24.
    Moore LE, Baris DR, Figueroa JD, Garcia-Closas M, Karagas MR, Schwenn MR, et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis. 2011;32:182–9. doi: 10.1093/carcin/bgq223.CrossRefPubMedGoogle Scholar
  25. 25.
    Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42:978–84. doi: 10.1038/ng.687.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ozbek YK, Oztürk T, Tüzüner BM, Calay Z, Ilvan S, Seyhan FM, et al. Combined effect of CYP1B1 codon 432 polymorphism and N-acetyltransferase 2 slow acetylator phenotypes in relation to breast cancer in the Turkish population. Anticancer Res. 2010;30:2885–9.PubMedGoogle Scholar
  27. 27.
    Zhong X, Hui C, Xiao-Ling W, Yan L, Na L. NAT2 polymorphism and gastric cancer susceptibility: a meta-analysis. Arch Med Res. 2010;41:275–80. doi: 10.1016/j.arcmed.2010.06.001.CrossRefPubMedGoogle Scholar
  28. 28.
    Klimčáková L, Habalová V, Sivoňová M, Nagy V, Šalagovič J, Židzik J. Effect of NAT2 gene polymorphism on bladder cancer risk in Slovak population. Mol Biol Rep. 2011;38:1287–93. doi: 10.1007/s11033-010-0228-6. Epub 2010 Jun 22.CrossRefPubMedGoogle Scholar
  29. 29.
    Cascorbi I, Brochkmoller J, Roots I. A C4887A polymorphism in exon 7 of human CYP1A1: population frequency, mutation linkages, and impact on lung cancer susceptibility. Cancer Res. 1996;56:4965–9.PubMedGoogle Scholar
  30. 30.
    Lemos MC, Cabrita FJ, Silva HA, Vivan M, Plácido F, Regateiro FJ. Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis. 1999;20:1225–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Krajinovic M, Richer C, Sinnett H, Labuda D, Sinnett D. Genetic polymorphisms of N-acetyltransferases 1 and 2 and gene-gene interaction in the susceptibility to childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2000;9:557–62.PubMedGoogle Scholar
  32. 32.
    Rollinson S, Roddam P, Willett E, Roman E, Cartwright R, Jack A, et al. NAT2 acetylator genotypes confer no effect on the risk of developing adult acute leukemia: a case-control study. Cancer Epidemiol Biomarkers Prev. 2001;10:567–8.PubMedGoogle Scholar
  33. 33.
    Gra OA, Glotov AS, Zhm K, Makarova OV, Nasedkina TV. Genetic polymorphism in GST, NAT2, and MTRR and susceptibility to childhood acute leukemia. Mol Biol. 2008;42:214–25.CrossRefGoogle Scholar
  34. 34.
    Ouerhani S, Nefzi MA, Menif S, Safra I, Douzi K, Fouzai C, et al. Influence of genetic polymorphisms of xenobiotic metabolizing enzymes on the risk of developing leukemia in a Tunisian population. Bull Cancer. 2011;98:95–106. doi: 10.1684/bdc.2011.1502.PubMedGoogle Scholar
  35. 35.
    Zanrosso CW, Emerenciano M, Faro A, Gonçalves BA, Mansur MB, Pombo-de-Oliveira MS. Genetic variability in N-acetyltransferase 2 gene determines susceptibility to childhood lymphoid or myeloid leukemia in Brazil. Leuk Lymphoma. 2012;53:323–7. doi: 10.3109/10428194.2011.619605.CrossRefPubMedGoogle Scholar
  36. 36.
    Silveira VS, Canalle R, Scrideli CA, Queiroz RG, Lopes LF, Tone LG. CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome. Mol Cell Biochem. 2012;364:217–23. doi: 10.1007/s11010-011-1220-8.CrossRefPubMedGoogle Scholar
  37. 37.
    Bonaventure A, Goujon-Bellec S, Rudant J, Orsi L, Leverger G, Baruchel A, et al. Maternal smoking during pregnancy, genetic polymorphisms of metabolic enzymes, and childhood acute leukemia: the ESCALE study (SFCE). Cancer Causes Control. 2012;23:329–45. doi: 10.1007/s10552-011-9882-9.CrossRefPubMedGoogle Scholar
  38. 38.
    Loken MR, Wells DA. Immuneflorescence of surface markers in flow cytometry: a practical approach. The practical approach series. Series editors: D Rickwood and BD Hames. Edited by MG ormerod; New York Oxford University press. 2000. 77–9.Google Scholar
  39. 39.
    Larsen JK: Measurement of cytoplasmic and nuclear antigens in flow cytometry: a practical approach. The practical approach series. Series editors: D Rickwood and BD Hames. Edited by MG ormerod; New York Oxford University press. 2000. 105–7.Google Scholar
  40. 40.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Cascorbi I, Brockmöller J, Mrozikiewicz PM, Müller A, Roots I. Arylamine N-acetyltransferase activity in man. Drug Metab Rev. 1999;31:489–502.CrossRefPubMedGoogle Scholar
  42. 42.
    Gross M, Kruisselbrink T, Anderson K, Lang N, McGovern P, Delongchamp R, et al. Distribution and concordance of N-acetyltransferase genotype and phenotype in an american population. Cancer Epidemiol Biomark Prev. 1999;8:683–92.Google Scholar
  43. 43.
    Alexander FE, Patheal SL, Biondi A, Brandalise S, Cabrera ME, Chan LC, et al. Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Cancer Res. 2001;61:2542–6.PubMedGoogle Scholar
  44. 44.
    Khan N, Pande V, Das A. NAT2 sequence polymorphisms and acetylation profiles in Indians. Pharmacogenomics. 2013;14:289–303. doi: 10.2217/pgs.13.2.CrossRefPubMedGoogle Scholar
  45. 45.
    Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Genetic polymorphisms of N-acetyltransferases 1 and 2 and gene-gene interaction in the susceptibility to childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomark Prev. 2000;9:557–62.Google Scholar
  46. 46.
    Migliorini G, Fiege B, Hosking FJ, Ma Y, Kumar R, Sherborne AL, et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood. 2013;122:3298–307. doi: 10.1182/blood-2013-03-491316.CrossRefPubMedGoogle Scholar
  47. 47.
    Zanrosso CW, Emerenciano M, Faro A, Gonçalves BA, Mansur MB, Pombo-de-Oliveira MS. Genetic variability in N-acetyltransferase 2 gene determines susceptibility to childhood lymphoid or myeloid leukemia in Brazil. Leuk Lymphoma. 2012;53:323–7. doi: 10.3109/10428194.2011.619605.CrossRefPubMedGoogle Scholar
  48. 48.
    Hickman D, Palamanda JR, Unadkat JD, Sim E. Enzyme kinetic properties of human recombinant arylamine N-acetyltransferase 2 allotypic variants expressed in Escherichia coli. Biochem Pharmacol. 1995;50:697–703.CrossRefPubMedGoogle Scholar
  49. 49.
    Cartwright RA, Glashan RW, Rogers HJ, Ahmad RA, Barham-Hall D, Higgins E, et al. Role of N-acetyltransferase phenotypes in bladder carcinogenesis: a pharmacogenetic epidemiological approach to bladder cancer. Lancet. 1982;2:842–5.CrossRefPubMedGoogle Scholar
  50. 50.
    Cascorbi I, Drakoulis N, Brockmöller J, Maurer A, Sperling K, Roots I. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity. Am J Hum Genet. 1995;57:581–92.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Azza M. Kamel
    • 1
  • Gamal T. A. Ebid
    • 1
  • Heba S. Moussa
    • 1
  1. 1.Clinical Pathology Department, NCICairo UniversityCairoEgypt

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