Molecular Biology Reports

, Volume 37, Issue 7, pp 3217–3226 | Cite as

N-acetyltransferase 1 and 2 gene sequence variants and risk of head and neck cancer

  • Semra Demokan
  • Yusufhan Suoglu
  • Mustafa Gözeler
  • Deniz Demir
  • Nejat DalayEmail author


Polymorphisms that alter the function of genes involved in the activation or detoxification of carcinogenic compounds can influence an individuals risk of developing cancer. Polymorphic changes modulating the acetylation capacity of the N-acetyltransferase (NAT) genes have been implicated in the risk of developing cancer. In this study the role of genetically determined individual NAT1 and NAT2 genotypes, haplotypes and haplotype combinations in the predisposition to head and neck cancer was investigated. Polymorphic regions of the NAT1 and NAT2 genes were analyzed in patients with head and neck cancer and healthy individuals by polymerase chain reaction-restriction fragment length polymorphism. Distribution of the genotypes, allele frequencies, diplotypes and haplotypes and correlation with clinical characteristics were evaluated. No association was observed between the NAT1*3, NAT1*10, NAT1*11, NAT2*5 and NAT2*6 genotypes and risk of head and neck cancer. The NAT2*7 slow genotype was associated with reduced risk of disease. A significant association was observed between the fast acetylator NAT2*4/NAT1*10 diplotype and risk of head and neck cancer. Combined haplotypes harboring the T1088A and C1095A variants characterizing the NAT1*10 allele were associated with increased risk. Our results suggest that NAT1 and NAT2 gene combinations may influence the risk of developing head and neck cancer.


NAT1 NAT2 Genotype Haplotype Head and neck cancer 



This work was supported by the Istanbul University Research Fund (Project Number: 368/03062005). We thank to Prof. Dr. Thomas Winkler for providing the statistics programme. The authors thank to Burak Erdamar, MD, for his assistance and coordinative support during the initial phase of the study.


  1. 1.
    Sturgis EM, Wei Q (2002) Genetic susceptibility—molecular epidemiology of head and neck cancer. Curr Opin Oncol 14:310–317CrossRefPubMedGoogle Scholar
  2. 2.
    Mohrenweiser HW (2004) Genetic variation and exposure related risk estimation: will toxicology enter a new era? DNA repair and cancer as a paradigm. Toxicol Pathol 32(Supp 1):136–145CrossRefPubMedGoogle Scholar
  3. 3.
    Millerill MC, Mohrenweiser HW, Bell DA (2001) Genetic variability in susceptibility and response to toxicants. Toxicol Lett 120:269–280CrossRefGoogle Scholar
  4. 4.
    Huang WY, Olshan AF, Scheartz SM, Berndt SI, Chen C, Llaca V, Chanock SJ, Fraumeni JF, Hayes RB (2005) Selected genetic polymorphsms in MGMT, XRCC1, XPD, and XRCC3 and risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev 14:1747–1753CrossRefPubMedGoogle Scholar
  5. 5.
    Harth V, Schafer M, Abel J, Maintz L, Neuhaus T, Besuden M, Primke R, Wilkesmann A, Their R, Vetter H, Ko YD, Brüning T, Bolt HM, Ickstadt K (2008) Head and neck squamous cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair. J Toxicol Environ Health A 71:887–897CrossRefPubMedGoogle Scholar
  6. 6.
    Tripathy CB, Roy N (2006) Meta-analysis of glutathione S-transferase M1 genotype and risk toward head and neck cancer. Head Neck 28:217–224CrossRefPubMedGoogle Scholar
  7. 7.
    Capolungo E, Almadori G, Concolino P, Bussu F, Santonocito C, Venditelli F, Galli J, Zuppi C, Ameglio F, Paludetti G, Giardina B (2007) GSTT1 and GSTM1 allelic polymorphisms in head and neck cancer patients from Italian Lazio region. Clin Chem Acta 376:174–178CrossRefGoogle Scholar
  8. 8.
    Neuhaus T, Ko YD, Lorenzen K, Fronhoffs S, Harth V, Brode P, Vetter H, Blt HM, Pesch B, Brüning T (2004) Association of cytochrome P4502E1 polymorphisms and head and neck cancer. Toxicol Lett 151:273–282CrossRefPubMedGoogle Scholar
  9. 9.
    Kowalski M, Przybylowska K, Rusin P, Olzewski S, Morawiec-Sztandera A, Bielecka-Kowalska A, Pietruszewska W, Mlynarski W, Szemaraj J, Majsterek I (2009) Genetic polymorphisms in DNA base excision repair gene XRCC1 and the risk of squamous cell carcinoma of the head and neck. J Exp Clin Cancer Res 13:28–37Google Scholar
  10. 10.
    Boccia S, Cadoni G, Sayed-Tabatabaei F, Volante M, Arzani D, De Lauretis A, Cattel C, Almadori G, van Duijn CM, Paludetti G, Ricciardi G (2008) CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer. J Cancer Res Clin Oncol 134:93–100CrossRefPubMedGoogle Scholar
  11. 11.
    Geissler SA, Olshan AF, Cai J, Weissler M, Smith J, Bell D (2005) Glutathione S-transferase polymorphisms and survival from head and neck cancer. Head Neck 27:232–242CrossRefGoogle Scholar
  12. 12.
    Boccia S, Boffetta P, Brennan P, Ricciardi G, Gianfagna F, Matsuo K, van Duijn CM, Hung RJ (2009) Meta-analyses of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer. Cancer Lett 273:55–61CrossRefPubMedGoogle Scholar
  13. 13.
    Chen K, Zhao H, Hu Z, Wang LE, Zhang W, Sturgis EM, Wei Q (2008) CASP8 polymorphisms and risk of squamous cell carcinoma of the head and neck. Clin Cancer Res 14:6343–6349CrossRefPubMedGoogle Scholar
  14. 14.
    Agundez JAG (2008) Polymorphisms of human N-acetyltransferases and cancer risk. Curr Drug Metab 9:520–531CrossRefPubMedGoogle Scholar
  15. 15.
    Fronhoffs S, Brüning T, Ortiz-Pallardo E, Bröde P, Koch B, Harth V, Sachinidis A, Bolt HM, Herberhold C, Vetter H, Ko Y (2001) Real-time PCR analysis of the N-acetyltransferase NAT1 allele *3,*4,*10,*11,*14 and *17 polymorphism in squamous cell cancer of head and neck. Carcinogenesis 22:1405–1412CrossRefPubMedGoogle Scholar
  16. 16.
    Boukouvala S, Sim E (2005) Structural analysis of the genes for human arylamine N-acetyltransferases and characterisation of alternative transcripts. Basic Clin Pharmacol Toxicol 96:343–351CrossRefPubMedGoogle Scholar
  17. 17.
    Jaskula-Sztul R, Sokolowski W, Gajecka M, Szyfter K (2001) Association of arylamine N-acetyltransferase (NAT1 and NAT2) genotypes with urinary bladder cancer risk. J Appl Genet 42:223–231CrossRefPubMedGoogle Scholar
  18. 18.
    Hein DW (2002) Molecular genetics and function of the NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res 506–507:65–77PubMedGoogle Scholar
  19. 19.
    Li D, Jiao L, Li Y, Doll MA, Hein DW, Bondy ML, Evans DB, Wolff RA, Lenzi R, Pisters PW, Abbruzzese JR, Hassan MM (2006) Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer. Carcinogenesis 27:103–111CrossRefPubMedGoogle Scholar
  20. 20.
    Varzim G, Monteiro E, Silva R, Pinheiro C, Lopes C (2002) Polymorphisms of arylamine N-acetyltransferase (NAT1 and NAT2) and larynx cancer susceptibility. ORL J Otorhinolaryngol Relat Spec 64:206–212PubMedGoogle Scholar
  21. 21.
    Bouchardy C, Mitrunen K, Wikman H, Husgafuel-Pursiainen K, Dayer P, Benhamou S, Hirvonen A (1998) N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk. Pharmacogenetics 8:291–298CrossRefPubMedGoogle Scholar
  22. 22.
    Katoh T, Boissy R, Nagata N, Kitagawa K, Kuroda Y, Itoh H, Kawamoto T, Bell DA (2000) Inherited polymorphism in the N-acetyltransferase 1 (NAT1) and 2 (NAT2) genes and susceptibility to gastric and colorectal adenocarcinoma. Int J Cancer 85:46–49CrossRefPubMedGoogle Scholar
  23. 23.
    Garcia-Closas M, Malats N, Siverman D, Dosemeci M, Kogewinas M, Hein DW, Tardon A, Serra C, Carrato A, Garcia Closas R, Lloreta J, Castano-Vinyals G, Yeager M, Welch R, Chanock S, Chatterjee N, Wacholder S, Samanic C, Tota M, Fernandez F, Real FX, Rothman N (2005) NAT2 slow acetylation, GSTM1 genotype and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 366:649–659CrossRefPubMedGoogle Scholar
  24. 24.
    Lee CN, Yu MC, Bai KJ, Chang JH, Fang CL, Hsu HL, Huang BS, Lu PC, Liu HE (2009) NAT2 fast acetylator genotypes are associated with an increased risk for lung cancer with wild type epidermal growth factor receptors in Taiwan. Lung Cancer 64:9–12CrossRefPubMedGoogle Scholar
  25. 25.
    Ambrosone CB, Kropp S, Yang J, Yao S, Shields PG, Chang-Claude J (2008) Cigarette smoking, N-acetyltransferase 2 genotypes and breast cancer risk: pooled analysis and meta-analysis. Cancer Epidemiol Biomarkers Prev 17:15–26CrossRefPubMedGoogle Scholar
  26. 26.
    Wachholder S, Rothman N, Caporaso N (2000) Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst 92:1151–1158CrossRefGoogle Scholar
  27. 27.
    Jiao L, Doll MA, Hein DW, Bondy ML, Hassan MM, Hixson JE, Abbruzzese JL, Li D (2007) Haplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancer. Cancer Epidemol Biomarkers Prev 16:2379–2386CrossRefGoogle Scholar
  28. 28.
    Ishibe N, Sinha R, Hein DW, Kulldorff M, Strickland P, Fretland AJ, Chow WH, Kadlubar FF, Lang NP, Rothman H (2002) Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas. Pharmacogenetics 12:145–150CrossRefPubMedGoogle Scholar
  29. 29.
    Katoh T, Inatomi H, Yang M, Kawamato T, Matsumota T, Bell DA (1999) Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) genes and risk of urothelial transitional cell carcinoma among Japanese. Pharmacogenetics 9:401–404CrossRefPubMedGoogle Scholar
  30. 30.
    Hein DW, Leff MA, Ishibe N, Sinha R, Frasier HA, Doll MA, Xiao GH, Weinrich MC, Caporaso NE (2002) Association of prostate cancer with rapid N-acetyltransferase 1 (NAT1*10) in combination with slow N-acetyltransferase 2 genotypes in a pilot case control study. Environ Mol Mut 40:161–167CrossRefGoogle Scholar
  31. 31.
    Krajinovic M, Ghadirian P, Richer C, Sinett H, Gandini S, Perret C, Lacroix A, Labuda D, Sinnett D (2001) Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions. Int J Cancer 92:220–225CrossRefPubMedGoogle Scholar
  32. 32.
    Wikman H, Thiel S, Jager B, Schmezer P, Spiegelhalder B, Edler L, Dienemann H, Kayser K, Schulz V, Drings P, Bartsch H, Risch A (2001) Relevance of N-acetyltransferase 1 and 2 (NAT1, NAT2) genetic polymorphisms in non-small cell lung cancer susceptibility. Pharmacogenetics 11:157–168CrossRefPubMedGoogle Scholar
  33. 33.
    Boissy RJ, Watson MA, Umbach DM, Deakin M, Elder J, Strange RC, Bell DA (2000) A pilot study investigating the role of NAT1 and NAT2 polymorphisms in gastric adenocarcinoma. Int J Cancer 87:507–511CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang XF, Bian JC, Zhang XY, Zhang ZM, Jiang F, Wang QM, Wang QJ, Cao YY, Tang BM (2005) Are polymorphisms of N-acetyltransferase genes susceptible to primary liver cancer in Luoyang, China? World J Gastroenterol 11:1457–1462PubMedGoogle Scholar
  35. 35.
    Lincz LF, Kerridge I, Scorgie FE, Bailey M, Enno A, Spencer A (2004) Xenobiotic gene polymorphisms and susceptibility to multiple myeloma. Haematologica 89:628–629PubMedGoogle Scholar
  36. 36.
    Lee KM, Park SK, Kim SU, Doll MA, Yoo KY, Ahn SH, Noh DY, Hirvonen A, Hein DW, Kang D (2003) N-acetyltransferase (NAT1, NAT2) and glutathione S-transferase (GSTM1, GSTT1) polymorphisms in breast cancer. Cancer Lett 196:179–186CrossRefPubMedGoogle Scholar
  37. 37.
    Chen J, Stampfer MJ, Hough HL, Garcia-Closas M, Willett WC, Hennekens CH, Kelsey KT, Hunter DJ (1998) A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer. Cancer Res 58:3307–3311PubMedGoogle Scholar
  38. 38.
    Cascorbi I, Roots I, Brockmoller J (2001) Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: significantly reduced risk in subjects with NAT1*10. Cancer Res 61:5051–5056PubMedGoogle Scholar
  39. 39.
    Henning S, Cascorbi I, Munchow B, Kahnke V, Roots I (1999) Association of arylamine N-acetyltransferases NAT1 and NAT2 genotypes to laryngeal cancer risk. Pharmacogenetics 9:103–111CrossRefPubMedGoogle Scholar
  40. 40.
    Frazier ML, O’Donnell FT, Kong S, Gu X, Campos I, Luthra R, Lynch PM, Amos CI (2001) Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. Cancer Res 61:1269–1271PubMedGoogle Scholar
  41. 41.
    Unal M, Tamer L, Akbas Y, Pata YS, Vayisoglu Y, Degirmenci U, Camdeviren H (2005) Genetic polymorphism of N-acetyltransferase 2 in the susceptibility to laryngeal squamous cell carcinoma. Head Neck 27:1056–1060CrossRefPubMedGoogle Scholar
  42. 42.
    Cascorbi I, Brockmoller J, Mrozikiewicz PM, Bauer S, Loddenkemper R, Roots I (1996) Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer. Cancer Res 56:3961–3966PubMedGoogle Scholar
  43. 43.
    Gajecka M, Rydzanicz M, Juskula-Sztul R, Kujawski M, Szyfter W, Szyfter K (2005) CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma. Mutat Res 574:112–123PubMedGoogle Scholar
  44. 44.
    Szyfter K, Szmeja Z, Szyfter W, Hemminki K, Banaszewski J, Jaskula-Sztul R, Louhelainen J (1999) Molecular and cellular alterations in tobacco smoke-associated larynx cancer. Mutat Res 445:259–274PubMedGoogle Scholar
  45. 45.
    Kocabas NA, Sardas S, Cholerton S, Daly AK, Karakaya AE (2004) N-acetyltransferase (NAT2) polymorphism and breast cancer susceptibility: a lack of association in a case-control study of Turkish population. Int J Toxicol 23:25–31CrossRefPubMedGoogle Scholar
  46. 46.
    Aynacioglu AS, Cascorbi I, Mrozikiewicz PM, Roots I (1997) Arylamine N-acetyltransferase (NAT2) genotypes in a Turkish population. Pharmacogenetics 7:327–331CrossRefPubMedGoogle Scholar
  47. 47.
    Borlak J, Reamon-Buettner SM (2006) N-acetyltransferase 2 (NAT2) gene polymorphisms in colon and lung cancer patients. BMC Med Genet 7:58CrossRefPubMedGoogle Scholar
  48. 48.
    Moslehi R, Chatterjee N, Church TR, Chen J, Yeager M, Weissfield J, Hein DW, Hayes RB (2006) Cigarette smoking: N-acetyltransferase genes and the risk of advanced colorectal adenoma. Pharmacogenomics 7:819–829CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Semra Demokan
    • 1
  • Yusufhan Suoglu
    • 2
  • Mustafa Gözeler
    • 2
  • Deniz Demir
    • 2
  • Nejat Dalay
    • 1
    Email author
  1. 1.Department of Basic OncologyI.U. Oncology InstituteCapa, IstanbulTurkey
  2. 2.Department of Otolaryngology, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey

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