Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study

Authors: Marco Matejcic, Matjaz Vogelsang, Yabing Wang, Iqbal M Parker

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Tobacco smoking and red meat consumption are some of the known risk factors associated with the development of oesophageal cancer. N-acetytransferases (NAT1 and NAT2) play a key role in metabolism of carcinogenic arylamines present in tobacco smoke and overcooked red meat. We hypothesized that NAT1 and NAT2 genetic polymorphisms may influence the risk of oesophageal cancer upon exposure to environmental carcinogens.

Methods

Single nucleotide polymorphisms (SNPs) in the NAT1 and NAT2 genes were investigated by genotyping 732 cases and 768 healthy individuals from two South African populations to deduce the acetylator phenotype (slow, intermediate or rapid) from the combination of the genotyped SNPs.

Results

The 341 CC genotype (rs1801280) was significantly associated with a reduced risk for oesophageal cancer in the Mixed Ancestry population (OR = 0.31; 95% CI 0.11-0.87). The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58). Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81). In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).

Conclusions

Our findings indicate that N-acetylation polymorphisms may modify the association between environmental risk factors and oesophageal cancer risk and that N-acetyltransferases may play a key role in detoxification of carcinogens. Prevention strategies in lifestyle and dietary habits may reduce the incidence of oesophageal cancer in high-risk populations.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Forman D, O'Brien M, Ferlay J, Center M, et al. Cancer burden in Africa and opportunities for prevention. Cancer. 2012;118:4372–84.CrossRefPubMed
2.
Sammon AM. Carcinogens and endemic squamous cancer of the oesophagus in Transkei, South Africa. Environmental initiation is the dominant factor; tobacco or other carcinogens of low potency or concentration are sufficient for carcinogenesis in the predisposed mucosa. Med Hypotheses. 2007;69:125–31.CrossRefPubMed
3.
4.
Dandara C, Li DP, Walther G, Parker MI. Gene-environment interaction: the role of SULT1A1 and CYP3A5 polymorphisms as risk modifiers for squamous cell carcinoma of the oesophagus. Carcinogenesis. 2006;27:791–7.CrossRefPubMed
5.
Islami F, Fedirko V, Tramacere I, Bagnardi V, Jenab M, Scotti L, et al. Alcohol drinking and esophageal squamous cell carcinoma with focus on light-drinkers and never-smokers: a systematic review and meta-analysis. Int J Cancer. 2011;129:2473–84.CrossRefPubMed
6.
Steevens J, Schouten LJ, Goldbohm RA, van den Brandt PA. Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort study. Gut. 2010;59:39–48.CrossRefPubMed
7.
Keszei AP, Schouten LJ, Goldbohm RA, van den Brandt PA. Red and processed meat consumption and the risk of esophageal and gastric cancer subtypes in The Netherlands Cohort Study. Ann Oncol. 2012;23:2319–26.CrossRefPubMed
8.
O’Doherty MG, Cantwell MM, Murray LJ, Anderson LA, Abnet CC, FINBAR Study Group. Dietary fat and meat intakes and risk of reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma. Int J Cancer. 2011;129:1493–502.CrossRefPubMedPubMedCentral
9.
Turesky RJ. Formation and biochemistry of carcinogenic heterocyclic aromatic amines in cooked meats. Toxicol Lett. 2007;168:219–27.CrossRefPubMed
10.
Jakszyn P, Agudo A, Ibáñez R, García-Closas R, Pera G, Amiano P, et al. Development of a food database of nitrosamines, heterocyclic amines, and polycyclic aromatic hydrocarbons. J Nutr. 2004;134:2011–4.PubMed
11.
Hein DW. Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res. 2002;506–507:65–77.CrossRefPubMed
12.
Hickman D, Risch A, Buckle V, Spurr NK, Jeremiah SJ, McCarthy A, et al. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochem J. 1994;297:441–5.CrossRefPubMedPubMedCentral
13.
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.PubMed
14.
Taja-Chayeb L, González-Fierro A, Miguez-Muñoz C, Trejo-Becerril C, Cruz-Hernandez Ede L, Cantu D, et al. Acetylator status and N-acetyltransferase 2 gene polymorphisms; phenotype-genotype correlation with the sulfamethazine test. Pharmacogenet Genomics. 2011;21:894–901.CrossRefPubMed
15.
Fretland AJ, Leff MA, Doll MA, Hein DW. Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms. Pharmacogenetics. 2001;11:207–15.CrossRefPubMed
16.
Hein DW, Doll MA. Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes. Pharmacogenomics. 2012;13:31–41.CrossRefPubMed
17.
Adams CH, Werely CJ, Victor TC, Hoal EG, Rossouw G, van Helden PD. Allele frequencies for glutathione S-transferase and N-acetyltransferase 2 differ in African population groups and may be associated with oesophageal cancer or tuberculosis incidence. Clin Chem Lab Med. 2003;41:600–5.CrossRefPubMed
18.
Zhu Y, States JC, Wang Y, Hein DW. Functional effects of genetic polymorphisms in the N-acetyltransferase 1 coding and 3' untranslated regions. Birth Defects Res A Clin Mol Teratol. 2011;91:77–84.CrossRefPubMedPubMedCentral
19.
Loktionov A, Moore W, Spencer SP, Vorster H, Nell T, O'Neill IK, et al. Differences in N-acetylation genotypes between Caucasians and Black South Africans: implications for cancer prevention. Cancer Detect Prev. 2002;26:15–22.CrossRefPubMed
20.
Wang D, Para MF, Koletar SL, Sadee W. Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity. Pharmacogenet Genomics. 2011;21:652–64.CrossRefPubMedPubMedCentral
21.
Zang Y, Doll MA, Zhao S, States JC, Hein DW. Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis. 2007;28:1665–71.CrossRefPubMedPubMedCentral
22.
Agúndez JA. Polymorphisms of human N-acetyltransferases and cancer risk. Curr Drug Metab. 2008;9:520–31.CrossRefPubMed
23.
Nöthlings U, Yamamoto JF, Wilkens LR, Murphy SP, Park SY, Henderson BE, et al. Meat and heterocyclic amine intake, smoking, NAT1 and NAT2 polymorphisms, and colorectal cancer risk in the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2009;18:2098–106.CrossRefPubMedPubMedCentral
24.
Morita S, Yano M, Tsujinaka T, Ogawa A, Taniguchi M, Kaneko K, et al. Association between genetic polymorphisms of glutathione S-transferase P1 and N-acetyltransferase 2 and susceptibility to squamous-cell carcinoma of the esophagus. Int J Cancer. 1998;79:517–20.CrossRefPubMed
25.
Shibuta J, Eto T, Kataoka A, Inoue H, Ueo H, Suzuki T, et al. Genetic polymorphism of N-acetyltransferase 2 in patients with esophageal cancer. Am J Gastroenterol. 2001;96:3419–24.CrossRefPubMed
26.
Jain M, Kumar S, Lal P, Tiwari A, Ghoshal UC, Mittal B. Association of genetic polymorphisms of N-acetyltransferase 2 and susceptibility to esophageal cancer in north Indian population. Cancer Invest. 2007;25:340–6.CrossRefPubMed
27.
Lee JM, Lee YC, Yang SY, Shi WL, Lee CJ, Luh SP, et al. Genetic polymorphisms of p53 and GSTP1, but not NAT2, are associated with susceptibility to squamous-cell carcinoma of the esophagus. Int J Cancer. 2000;89:458–64.CrossRefPubMed
28.
Malik MA, Upadhyay R, Modi DR, Zargar SA, Mittal B. Association of NAT2 gene polymorphisms with susceptibility to esophageal and gastric cancers in the Kashmir Valley. Arch Med Res. 2009;40:416–23.CrossRefPubMed
29.
Wideroff L, Vaughan TL, Farin FM, Gammon MD, Risch H, Stanford JL, et al. GST, NAT1, CYP1A1 polymorphisms and risk of esophageal and gastric adenocarcinomas. Cancer Detect Prev. 2007;31:233–6.CrossRefPubMedPubMedCentral
30.
de Wit E, Delport W, Rugamika CE, Meintjes A, Möller M, van Helden PD, et al. Genome-wide analysis of the structure of the South African Coloured Population in the Western Cape. Hum Genet. 2010;128:145–53.CrossRefPubMed
31.
Gustafson S, Proper JA, Bowie EJ, Sommer SS. Parameters affecting the yield of DNA from human blood. Anal Biochem. 1987;165:294–9.CrossRefPubMed
32.
Doll MA, Hein DW. Rapid genotype method to distinguish frequent and/or functional polymorphisms in human N-acetyltransferase-1. Anal Biochem. 2002;301:328–32.CrossRefPubMed
33.
Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–14.CrossRefPubMedPubMedCentral
34.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.CrossRefPubMed
35.
36.
Meyer D, Parkin DP, Seifart HI, Maritz JS, Engelbrecht AH, Werely CJ, et al. NAT2 slow acetylator function as a risk indicator for age-related cataract formation. Pharmacogenetics. 2003;13:285–9.CrossRefPubMed
37.
Smelt VA, Mardon HJ, Sim E. Placental expression of arylamine N-acetyltransferases: evidence for linkage disequilibrium between NAT1*10 and NAT2*4 alleles of the two human arylamine N-acetyltransferase loci NAT1 and NAT2. Pharmacol Toxicol. 1998;83:149–57.CrossRefPubMed
38.
Cascorbi I, Roots I, Brockmöller J. Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: Significantly reduced risk in subjects with NAT1*10. Cancer Res. 2001;61:5051–6.PubMed
39.
Pacella-Norman R, Urban MI, Sitas F, Carrara H, Sur R, Hale M, et al. Risk factors for oesophageal, lung, oral and laryngeal cancers in black South Africans. Br J Cancer. 2002;86:1751–6.CrossRefPubMedPubMedCentral
40.
Hein DW, Doll MA, Rustan TD, Ferguson RJ. Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Res. 1995;55:3531–6.PubMed
41.
Wang L, Tang W, Chen S, Sun Y, Fan Y, Shi Y, et al. N-acetyltransferase 2 polymorphisms and risk of esophageal cancer in a Chinese population. PLoS One. 2014;9:e87783.CrossRefPubMedPubMedCentral
42.
Skog K, Solyakov A. Heterocyclic amines in poultry products: a literature review. Food Chem Toxicol. 2002;40:1213–21.CrossRefPubMed
43.
González CA, Jakszyn P, Pera G, Agudo A, Bingham S, Palli D, et al. Meat intake and risk of stomach and esophageal adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2006;98:345–54.CrossRefPubMed
44.
Jakszyn P, Luján-Barroso L, Agudo A, Bueno-de-Mesquita HB, Molina E, Sánchez MJ, et al. Meat and heme iron intake and esophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study. Int J Cancer. 2013;133:2744–50.PubMed
45.
Tappel A. Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases. Med Hypotheses. 2007;68:562–4.CrossRefPubMed
46.
Cross AJ, Pollock JR, Bingham SA. Haem, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat. Cancer Res. 2003;63:2358–60.PubMed
47.
Seitz HK, Stickel F, Homann N. Pathogenetic mechanisms of upper aerodigestive tract cancer in alcoholics. Int J Cancer. 2004;108:483–7.CrossRefPubMed
48.
Salaspuro M. Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. Scand J Gastroenterol. 2009;44:912–25.CrossRefPubMed
49.
Chen C, Ricks S, Doody DR, Fitzgibbons ED, Porter PL, Schwartz SM. N-Acetyltransferase 2 polymorphisms, cigarette smoking and alcohol consumption, and oral squamous cell cancer risk. Carcinogenesis. 2001;22:1993–9.CrossRefPubMed
50.
Yukawa Y, Ohashi S, Amanuma Y, Nakai Y, Tsurumaki M, Kikuchi O, et al. Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. Am J Cancer Res. 2014;4:279–84.PubMedPubMedCentral
Metadata
Title
NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study
Authors
Marco Matejcic
Matjaz Vogelsang
Yabing Wang
Iqbal M Parker
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1105-4

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Case report

The diagnostic challenge of pulmonary tumour thrombotic microangiopathy as a presentation for metastatic gastric cancer: a case report and review of the literature

Research article

Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan

Research article

Circulating tumor cells (CTC) and KRAS mutant circulating free DNA (cfDNA) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer

Research article

Novel non-invasive biomarkers that distinguish between benign prostate hyperplasia and prostate cancer

Research article

Shifts in subsets of CD8+ T-cells as evidence of immunosenescence in patients with cancers affecting the lungs: an observational case-control study

Research article

MicroRNA-363 targets myosin 1B to reduce cellular migration in head and neck cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits