Skip to main content

Advertisement

SpringerLink
Log in

The rs1801280 SNP is associated with non-small cell lung carcinoma by exhibiting a highly deleterious effect on N-acetyltransferase 2

  • Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

N-acetyltransferase 2 is an enzyme that is involved in the detoxification of carcinogens in the human body, so any damage to this protein may lead to the emergence of several metabolic dysfunctions. This work was conducted to determine the association between NAT2 polymorphism and non-small cell lung carcinoma (NSCLC) that is increasingly reported in the Iraqi population.

Methods

PCR sequencing was conducted to assess the possible association between genetic variants and NSCLC. Several in silico tools were implemented to investigate the effect of the observed SNPs on the structure, function, and stability of the altered NAT2.

Results

Five SNPS of NAT2 (rs1208, rs1041983, rs1799929, rs1799930, and rs1801280) were identified in high frequencies in the amplified fragment. These SNPs showed variable distributions of haplotypes between cases and controls. No significant association of rs1208, rs1041983, rs1799929, and rs1799930 with NSCLC was shown in the investigated population. In contrast, rs1801280: CC genotype showed a highly significant (P = 0.009) association with the NSCLC, and individuals with this genotype had 2.19 more chances for developing NSCLC (OR 2.19; Cl95% 1.21–3.94). Association analysis of rs1801280 SNP distribution among the investigated patients showed that patients with CC genotype showed a significant (P = 0.02, OR 2.65) association with family history, which entailed a high hereditary possibility of this genotype among Iraqi patients. It was predicted that this SNP showed high damaging effects on the activity of NAT2 enzyme, with various deleterious outcomes on enzyme structure, function, and stability.

Conclusion

Data indicated that rs1801280 SNP exerted a tight association with NSCLC since individuals with CC genotype exhibited the most damaging effects on the NAT2 that may be behind the low acetylation rates of this enzyme in patients with NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The data stated in this work are confidential, as stipulated by the University of Kufa Institutional Review Board. The medical record was analyzed with the permission of Merjan Cancer Center’s medical board direction. Genotyping data are available on request at the Laboratory of Biotechnology supervised by Professor Mohammed Baqur S Al-Shuhaib (Al-Qasim Green University, Iraq mohammed79@agre.uoqasim.edu.iq). All information that supports our findings are included in this article.

Code availability

All data generated or analyzed during this work are included in this published article.

References

  • Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 76:7–20

    Google Scholar 

  • Al-Shuhaib MBS (2017) A universal, rapid, and inexpensive method for genomic DNA isolation from the whole blood of mammals and birds. J Genet 96:171–176

    Article  CAS  Google Scholar 

  • Al-Shuhaib MBS (2019) A comprehensive in silico prediction of the most deleterious missense variants in the bovine LEP gene. Biotechnologia 100:429–439

    Article  CAS  Google Scholar 

  • Al-Shuhaib MBS (2020) The deleterious F109S mutation disrupts binding of sex-determining region Y with DNA. Karbala Int J Mod Sci 6:385–395

    Article  Google Scholar 

  • Altman DG (1991) Practical staticts for medical research, 1st edn. Chapman and Hall/CRC Press, London

    Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  Google Scholar 

  • Capriotti E, Calabrese R, Casadio R (2006) Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22:2729–2734

    Article  CAS  Google Scholar 

  • Choi R, Jeong B-H, Koh W-J, Lee S-Y (2017) Recommendations for optimizing tuberculosis treatment: therapeutic drug monitoring, pharmacogenetics, and nutritional status considerations. Ann Lab Med 37:97–107

    Article  CAS  Google Scholar 

  • Choi Y, Sims GE, Murphy S et al (2012) Predicting the functional effect of amino acid substitutions and indels. PLoS ONE 7:e46688

    Article  CAS  Google Scholar 

  • Diaz-Lagares A, Mendez-Gonzalez J, Hervas D et al (2016) A novel epigenetic signature for early diagnosis in lung cancer. Clin Cancer Res 22:3361–3371

    Article  CAS  Google Scholar 

  • El-Baz A, Gimel’farb G, Falk R et al (2009) Toward early diagnosis of lung cancer. International Conference on Medical Image Computing and Computer-Assisted Intervention. Springer, Berlin, Heidelberg, pp 682–689

    Google Scholar 

  • Ferguson RJ, Doll MA, Rustan TD et al (1994) Cloning, expression, and functional characterization of two mutant (NAT2 (191) and NAT2 (341/803)) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles. Drug Metab Dispos 22:371–376

    CAS  Google Scholar 

  • Fernandes MR, De Carvalho DC, dos Santos ÂKCR et al (2013) Association of slow acetylation profile of NAT2 with breast and gastric cancer risk in Brazil. Anticancer Res 33:3683–3689

    CAS  Google Scholar 

  • Gao H, Niu Y, Li M et al (2017) Identification of DJ-1 as a contributor to multidrug resistance in human small-cell lung cancer using proteomic analysis. Int J Exp Pathol 98:67–74

    Article  CAS  Google Scholar 

  • Garcia-Closas M, Malats N, Real FX et al (2004) NAT2 slow acetylation and GSTM1 null genotype increase bladder cancer risk: confirmatory results from the spanish bladder cancer study. Lancet 366:649–659

    Article  Google Scholar 

  • Hamann HA, Ver Hoeve ES, Carter-Harris L et al (2018) Multilevel opportunities to address lung cancer stigma across the cancer control continuum. J Thorac Oncol 13:1062–1075

    Article  Google Scholar 

  • Hecht JT, Ester A, Scott A et al (2007) NAT2 variation and idiopathic talipes equinovarus (clubfoot). Am J Med Genet Part A 143:2285–2291

    Article  Google Scholar 

  • Hegele RA, Kwan K, Harris SB et al (2000) NAT2 polymorphism associated with plasma glucose concentration in Canadian Oji-Cree. Pharmacogenet Genomics 10:233–238

    Article  CAS  Google Scholar 

  • Hein DW (2002) Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res Mol Mech Mutagen 506:65–77

    Article  Google Scholar 

  • Hein DW (2006) N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene 25:1649–1658

    Article  CAS  Google Scholar 

  • Henschke CI, McCauley DI, Yankelevitz DF et al (1999) Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 354:99–105

    Article  CAS  Google Scholar 

  • Huang C, Huang M, Chen W et al (2015) N-acetylglucosaminyltransferase V modulates radiosensitivity and migration of small cell lung cancer through epithelial–mesenchymal transition. FEBS J 282:4295–4306

    Article  CAS  Google Scholar 

  • Hussain AMA, Lafta RK (2021) Cancer trends in Iraq 2000–2016. Oman Med J 36:e219

    Article  Google Scholar 

  • Ittisoponpisan S, Islam SA, Khanna T et al (2019) Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated? J Mol Biol 431:2197–2212

    Article  CAS  Google Scholar 

  • Jarrar YB, Balasmeh AA, Jarrar W (2018) Sequence analysis of the N-acetyltransferase 2 gene (NAT2) among Jordanian volunteers. Libyan J Med 13:1408381

    Article  Google Scholar 

  • Jazieh AR, Algwaiz G, Errihani H et al (2019) Lung cancer in the Middle East and North Africa region. J Thorac Oncol 14:1884–1891

    Article  Google Scholar 

  • Kasajova P, Holubekova V, Mendelova A et al (2016) Active cigarette smoking and the risk of breast cancer at the level of N-acetyltransferase 2 (NAT2) gene polymorphisms. Tumor Biol 37:7929–7937

    Article  CAS  Google Scholar 

  • Khlifi R, Messaoud O, Rebai A, Hamza-Chaffai A (2013) Polymorphisms in the human cytochrome P450 and arylamine N-acetyltransferase: susceptibility to head and neck cancers. Biomed Res Int 2013:582768

    Article  Google Scholar 

  • Lavender N, Hein DW, Brock G, Kidd LCR (2015) Evaluation of oxidative stress response related genetic variants, pro-oxidants, antioxidants and prostate cancer. AIMS Med Sci 2:271

    Article  Google Scholar 

  • Lee M-R, Huang H-L, Lin S-W et al (2019) Isoniazid concentration and NAT2 genotype predict risk of systemic drug reactions during 3HP for LTBI. J Clin Med 8:812

    Article  CAS  Google Scholar 

  • Liao Y, Yin G, Wang X et al (2019) Identification of candidate genes associated with the pathogenesis of small cell lung cancer via integrated bioinformatics analysis. Oncol Lett 18:3723–3733

    CAS  Google Scholar 

  • Liu F, Zhang N, Zhou X et al (2006) Arylamine N-acetyltransferase aggregation and constitutive ubiquitylation. J Mol Biol 361:482–492

    Article  CAS  Google Scholar 

  • López-Ferrando V, Gazzo A, De La Cruz X et al (2017) PMut: a web-based tool for the annotation of pathological variants on proteins, 2017 update. Nucleic Acids Res 45:W222–W228

    Article  Google Scholar 

  • Martinez-Gonzalez LJ, Antúnez-Rodríguez A, Vazquez-Alonso F et al (2020) Genetic variants in xenobiotic detoxification enzymes, antioxidant defenses and hormonal pathways as biomarkers of susceptibility to prostate cancer. Sci Total Environ 730:138314

    Article  CAS  Google Scholar 

  • Matejcic M, Vogelsang M, Wang Y, Parker IM (2015) NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study. BMC Cancer 15:150

    Article  Google Scholar 

  • McDonagh EM, Boukouvala S, Aklillu E et al (2014) PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenet Genomics 24:409

    Article  CAS  Google Scholar 

  • Magalon H, Patin E, Austerlitz F et al (2008) Population genetic diversity of the NAT2 gene supports a role of acetylation in human adaptation to farming in Central Asia. Eur J Hum Genet 16:243–251

    Article  CAS  Google Scholar 

  • Mitchell KR, Warshawsky D (2003) Xenobiotic inducible regions of the human arylamine N-acetyltransferase 1 and 2 genes. Toxicol Lett 139:11–23

    Article  CAS  Google Scholar 

  • Mohamed S, Bayoumi H, El-Aziz NA et al (2018) Prevalence, risk factors, and impact of lung Cancer on outcomes of idiopathic pulmonary fibrosis: a study from the Middle East. Multidiscip Respir Med 13:1–7

    Article  Google Scholar 

  • Morton LM, Bernstein L, Wang SS et al (2007) Hair dye use, genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma. Carcinogenesis 28:1759–1764

    Article  CAS  Google Scholar 

  • Ng PC, Henikoff S (2006) Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet 7:61–80

    Article  CAS  Google Scholar 

  • Ochs-Balcom HM, Wiesner G, Elston RC (2007) A meta-analysis of the association of N-acetyltransferase 2 gene (NAT2) variants with breast cancer. Am J Epidemiol 166:246–254

    Article  Google Scholar 

  • Patin E, Barreiro LB, Sabeti PC et al (2006) Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. Am J Hum Genet 78:423–436

    Article  CAS  Google Scholar 

  • Petrosino M, Novak L, Pasquo A et al (2021) Analysis and interpretation of the impact of missense variants in cancer. Int J Mol Sci 22:5416

    Article  CAS  Google Scholar 

  • DE Pires V, Ascher DB, Blundell TL (2014a) mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics 30:335–342

    Article  CAS  Google Scholar 

  • DE Pires V, Ascher DB, Blundell TL (2014b) DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res 42:W314–W319

    Article  CAS  Google Scholar 

  • Pshennikova VG, Barashkov NA, Romanov GP et al (2019) Comparison of predictive in silico tools on missense variants in GJB2, GJB6, and GJB3 genes associated with autosomal recessive deafness 1A (DFNB1A). Sci World J 2019:5198931

    Article  Google Scholar 

  • Rogers TK (2019) Minimising diagnostic delay in lung cancer. Thorax 74:319–320

    Article  Google Scholar 

  • Rosenberger A, Illig T, Korb K et al (2008) Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years. BMC Cancer 8:60

    Article  Google Scholar 

  • Ruiz JD, Martínez C, Anderson K et al (2012) The differential effect of NAT2 variant alleles permits refinement in phenotype inference and identifies a very slow acetylation genotype. PLoS ONE 7:e44629

    Article  CAS  Google Scholar 

  • Salazar-González RA, Doll MA, Hein DW (2020) Human arylamine N-acetyltransferase 2 genotype-dependent protein expression in cryopreserved human hepatocytes. Sci Rep 10:7566

    Article  Google Scholar 

  • Salim EI, Jazieh AR, Moore MA (2011) Lung cancer incidence in the Arab league countries: risk factors and control. Asian Pac J Cancer Prev 12:17–34

    Google Scholar 

  • Schoonjans F, Zalata A, Depuydt CE, Comhaire FH (1995) MedCalc: a new computer program for medical statistics. Comput Methods Programs Biomed 48:257–262

    Article  CAS  Google Scholar 

  • Schrödinger L, DeLano W (2020) PyMOL. PyMOL Mol Graph Syst Version 2

  • Selinski S, Blaszkewicz M, Ickstadt K et al (2013) Refinement of the prediction of N-acetyltransferase 2 (NAT2) phenotypes with respect to enzyme activity and urinary bladder cancer risk. Arch Toxicol 87:2129–2139

    Article  CAS  Google Scholar 

  • Sillanpää P, Hirvonen A, Kataja V et al (2005) NAT2 slow acetylator genotype as an important modifier of breast cancer risk. Int J Cancer 114:579–584

    Article  Google Scholar 

  • Sim E, Walters K, Boukouvala S (2008) Arylamine N-acetyltransferases: from structure to function. Drug Metab Rev 40(3):479–510

    Article  CAS  Google Scholar 

  • Song Y, Qi X, Liu X (2020) N-acetyltransferase 2 polymorphism is associated with bladder cancer risk: an updated meta-analysis based on 54 case-control studies. Gene 757:144924

    Article  CAS  Google Scholar 

  • Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    Article  Google Scholar 

  • Tang H, Thomas PD (2016) PANTHER-PSEP: predicting disease-causing genetic variants using position-specific evolutionary preservation. Bioinformatics 32:2230–2232

    Article  CAS  Google Scholar 

  • Tiis RP, Osipova LP, Lichman DV et al (2020) Studying polymorphic variants of the NAT2 gene (NAT2* 5 and NAT2* 7) in Nenets populations of Northern Siberia. BMC Genet 21:115

    Article  CAS  Google Scholar 

  • Venselaar H, Te Beek TAH, Kuipers RKP et al (2010) Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 11:548

    Article  Google Scholar 

  • Walia HK, Singh N, Sharma S (2021) Association of NAT-2 gene polymorphisms toward lung cancer susceptibility and prognosis in North Indian patients treated with platinum-based chemotherapy. Pharmacogenomics 23:97–118

    Article  Google Scholar 

  • Wen J, Xu Q, Yuan Y (2018) Single nucleotide polymorphisms and sporadic colorectal cancer susceptibility: a field synopsis and meta-analysis. Cancer Cell Int 18:155

    Article  CAS  Google Scholar 

  • Wong M, Lao XQ, Ho K-F et al (2017) Incidence and mortality of lung cancer: global trends and association with socioeconomic status. Sci Rep 7:14300

    Article  Google Scholar 

  • Worth CL, Preissner R, Blundell TL (2011) SDM—a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res 39:W215–W222

    Article  CAS  Google Scholar 

  • Wu H, Dombrovsky L, Tempel W et al (2007) Structural basis of substrate-binding specificity of human arylamine N-acetyltransferases. J Biol Chem 282:30189–30197

    Article  CAS  Google Scholar 

  • Ye J, Coulouris G, Zaretskaya I et al (2012) Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 13:134

    Article  CAS  Google Scholar 

  • Yuliwulandari R, Susilowati RW, Wicaksono BD et al (2016) NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet 61:533–537

    Article  CAS  Google Scholar 

  • Zang Y, Zhao S, Doll MA, Hein DW (2004) The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation. Pharmacogenet Genomics 14:717–723

    Article  CAS  Google Scholar 

  • Zawadzka I, Jeleń A, Pietrzak J et al (2020) The impact of ABCB1 gene polymorphism and its expression on non-small-cell lung cancer development, progression and therapy–preliminary report. Sci Rep 10:6188

    Article  CAS  Google Scholar 

  • Zhou X, Ma Z, Dong D, Wu B (2013) Arylamine N-acetyltransferases: a structural perspective. Br J Pharmacol 169:748–760

    Article  CAS  Google Scholar 

  • Zhu K, Xu A, Xia W et al (2021) Association between NAT2 polymorphism and lung cancer risk: a systematic review and meta-analysis. Front Oncol 11:567762

    Article  Google Scholar 

  • Zhu X, Liu Y, Chen G et al (2019) Association between NAT2 polymorphisms and acute leukemia risk: a meta-analysis. Medicine (baltimore) 98:e14942

    Article  CAS  Google Scholar 

  • Zienolddiny S, Campa D, Lind H et al (2008) A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers. Carcinogenesis 29:1164–1169

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge all the partnerships and all patients that engaged voluntarily, and who made this study possible. The Middle-Euphrates Cancer Center (MECC), Najaf province, and Merjan Cancer Center (MCC), Babil province for granting the samples and postgraduate laboratory unit, College of Medicine, University of Kufa for providing some facilities to accompany the preliminary samples preparations.

Funding

This work was part of PhD thesis of ZKA prepared in the Higher Institute of Biotechnology of Sfax, 3000 Sfax University, Tunisia (IQ200476). The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Biology, College of Science, University of Kufa, Najaf, 54001, Iraq

    Zahraa K. Lawi

  2. Department of Animal Production, College of Agriculture, Al-Qasim Green University, Al-Qasim-8, Babil, 51001, Iraq

    Mohammed Baqur S. Al-Shuhaib

  3. Higher Institute of Biotechnology of Sfax, Sfax University, Sfax, 3000, Tunisia

    Ibtissem Ben Amara

Authors
  1. Zahraa K. Lawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammed Baqur S. Al-Shuhaib
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ibtissem Ben Amara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Samples collection and genotyping experiments were conducted by ZKA. DNA sequencing data, biostatistical calculations, and manuscript writing were conducted by MBSA. The study was supervised by TMA. All authors approved the final version of this work.

Corresponding author

Correspondence to Mohammed Baqur S. Al-Shuhaib.

Ethics declarations

Conflict of interest

No conflict of interest is reported by the authors.

Ethical approval

Institutional Ethics Committee Involving Humans of the University of Kufa (Najaf, Iraq) ratified this study (IECIH/UOK 088/2020; CAAE 08802212). All subjects signed a written informed consent form before participation and the study was conducted in accordance with Helsinki’s Declaration.

Consent to participate

All subjects signed a written informed consent form before participation and the work was conducted in accordance with Helsinki’s Declaration.

Consent for publication

All subjects signed a written informed consent form that consents to publication of the data.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lawi, Z.K., Al-Shuhaib, M.B.S. & Amara, I.B. The rs1801280 SNP is associated with non-small cell lung carcinoma by exhibiting a highly deleterious effect on N-acetyltransferase 2. J Cancer Res Clin Oncol 149, 147–157 (2023). https://doi.org/10.1007/s00432-022-04332-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-022-04332-3

Keywords

Search

Navigation