Skip to main content

Advertisement

SpringerLink
Log in

Frequencies of EGFR single nucleotide polymorphisms in non-small cell lung cancer patients and healthy individuals in the Republic of Serbia: a preliminary study

  • Original Article
  • Published:
Tumor Biology

Abstract

The purpose of this study was to determine the frequencies of EGFR −216G>T, −191C>A, and 181946C>T in Serbian non-small cell lung cancer (NSCLC) patients, as well as to compare it with healthy individuals, in order to assess their potential importance for lung cancer in Serbia. The study involved 56 NSCLC patients and 53 unrelated healthy volunteers, and genotyping was performed on DNA samples obtained from formalin-fixed paraffin-embedded lung tumor tissue and blood, respectively. This was the first time to show genotype frequencies of those single nucleotide polymorphisms for this study group from the territory of the Republic of Serbia. There was very strong evidence of association between age and death due to lung cancer (Pearson chi-square = 43.439, df = 2, p < 0,001), as well as between ever smoking and death due to lung cancer (Pearson chi-square = 31.727, df = 1, p < 0.001). When dominant genetic model (GG vs. GT+TT) was used for −216G>T, we have found significant association (p = 0.012) between −216GG genotype and NSCLC patients within smokers’ subgroup. So, carriers of −216GG genotype had higher risk (OR = 4.33, 95 % CI = 1.324–14.179) than noncarriers (GT and TT) for developing non-small cell lung cancer in our patients.

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

References

  1. Kumar A, Petri ET, Halmos B, Boggon TJ. The structure and clinical relevance of the EGF receptor in human cancer. J Clin Oncol. 2008;26(10):1742–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nie W, Tang L, Zhang H, Shao J, Wang Y, Chen L, et al. Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy. Int J Oncol. 2012;40(6):1763–9.

    CAS  PubMed  Google Scholar 

  3. Kim L, Liu G, Tsao MS. Predictive tumor biomarkers for EGFR inhibitors. In: Roth JA, Hong WK, Komaki RU, editors. Lung cancer, fourth edition. 2014. p. 435–53.

    Chapter  Google Scholar 

  4. Cooper WA, Lam DCL, O’Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013;5(5):S479–90.

    PubMed  PubMed Central  Google Scholar 

  5. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90.

    Article  CAS  PubMed  Google Scholar 

  6. Rajalingam K, Schreck R, Rapp UR, Albert Š. Ras oncogenes and their downstream targets. Biochimica et Biophysica Acta (BBA)-Molecular Cell Res. 2007;1773(8):1177–95.

    Article  CAS  Google Scholar 

  7. Brambilla E, Gazdar A. Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur Respir J. 2009;33(6):1485–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan SK, Gullicka WJ, Hill ME. Mutations of the epidermal growth factor receptor in non-small cell lung cancer—search and destroy. Eur J Cancer. 2006;42:17–23.

    Article  CAS  PubMed  Google Scholar 

  9. Liu G, Gurubhagavatula S, Zhou W, Wang Z, Yeap BY, Asomaning K, et al. Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. Pharmacogenomics J. 2008;8(2):129–38.

    Article  CAS  PubMed  Google Scholar 

  10. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.

    Article  CAS  PubMed  Google Scholar 

  11. Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011;63(2):437–59.

    Article  CAS  PubMed  Google Scholar 

  12. Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616–22.

    Article  CAS  PubMed  Google Scholar 

  13. Jung M, Cho BC, Lee CH, Park HS, Kang YA, Kim SK, et al. EGFR polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI. Yonsei Med J. 2012;53(6):1128–35.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Liu W, Innocenti F, Chen P, Das S, Cook Jr EH, Ratain MJ. Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clin Cancer Res. 2003;9:1009–12.

    CAS  PubMed  Google Scholar 

  15. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46.

    Article  CAS  PubMed  Google Scholar 

  16. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Final results from a phase II trial of ZD1839 (‘Iressa’) for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol. 2002;21:298a.

    Google Scholar 

  17. Ling WH, Lee SC. Inter-ethnic differences-how important is it in cancer treatment? AnnAcad Med Singapore. 2011;40(8):356–61.

    Google Scholar 

  18. Choi JE, Park SH, Kim KM, Lee WK, Kam S, Cha SI, et al. Polymorphisms in the epidermal growth factor receptor gene and the risk of primary lung cancer: a case-control study. BMC Cancer. 2007;7:199.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu W, Wu X, Zhang W, Montenegro RC, Fackenthal DL, Spitz JA, et al. Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NCI60 cell lines. Clin Cancer Res. 2007;13:6788–95.

    Article  CAS  PubMed  Google Scholar 

  20. Ma F, Sun T, Shi Y, Yu D, Tan W, Yang M, et al. Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with gefitinib. Lung Cancer. 2009;66(1):114–9.

    Article  PubMed  Google Scholar 

  21. Nomura M, Shigematsu H, Li L, Suzuki M, Takahashi T, Estess P, et al. Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers. PloSMed. 2007;4, e125.

    Google Scholar 

  22. Liu W, Innocenti F, Wu MH, Desai AA, Dolan ME, Cook Jr EH, et al. A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. Cancer Res. 2005;65(1):46–53.

    CAS  PubMed  Google Scholar 

  23. Obradovic J, Jurisic V, Tosic N, Mrdjanovic J, Perin B, Pavlovic S, et al. Optimization of PCR conditions for amplification of GC-rich EGFR promoter sequence. J Clin Lab Anal. 2013;27(6):487–93.

    Article  CAS  PubMed  Google Scholar 

  24. Excoffier L, Laval G, Schneider S. Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online. 2005;1:47–50.

    CAS  Google Scholar 

  25. Demographic Yearbook in the Republic of Serbia, 2013; ISSN 0084–4357; Published by: Statistical Office of the Republic of Serbia, Belgrade, 5 Milana Rakića St; For publishers: Prof. Dragan Vukmirovic, Ph.D, Director; 1–363

  26. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40(5):616–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ma Y, Liu X, Zhu J, Li W, Guo L, Han X, et al. Polymorphisms of co-inhibitory molecules (CTLA-4/PD-1/PD-L1) and the risk of non-small cell lung cancer in a Chinese population. Int J Clin Exp Med. 2015;8(9):16585–91.

    PubMed  PubMed Central  Google Scholar 

  28. Masroor M, Amit J, Javid J, Mir R, Prasant Y, Imtiyaz A, et al. Clinical implication of EGF A61G polymorphism in the risk of non small cell lung adenocarcinoma patients: a case control study. Asian Pac J Cancer Prev. 2015;16(17):7529–34.

    Article  PubMed  Google Scholar 

  29. Reference SNP (refSNP) Cluster report rs 712829; Short Genetic Variations Database. [Internet] (Available from: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=712829), accessed: January, 23, 2016. a

  30. Reference SNP (refSNP) Cluster report rs 712830; Short Genetic Variations Database. [Internet] (Available from: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=712830), accessed: January, 23, 2016. b

  31. Reference SNP (refSNP) Cluster report rs 2293347; Short Genetic Variations Database. [Internet] (Available from: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2293347), accessed: January, 23, 2016. c

  32. Ichihara S, Toyooka S, Fujiwara Y, Hotta K, Shigematsu H, Tokumo M, et al. The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Int J Cancer. 2007;120(6):1239–47.

    Article  CAS  PubMed  Google Scholar 

  33. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  34. Johnson AC, Ishii S, Jinno Y, Pastan I, Merlino GT. Epidermal growth factor receptor gene promoter. Deletion analysis and identification of nuclear protein binding sites. J Biol Chem. 1988;263:5693–9.

    CAS  PubMed  Google Scholar 

  35. Kageyama R, Merlino GT, Pastan I. Epidermal growth factor (EGF) receptor gene transcription: requirement for Sp1 and an EGF receptor-specific factor. J Biol Chem. 1988;263:6329–63236.

    CAS  PubMed  Google Scholar 

  36. Wu X, Zhao H, Suk R, Christiani DC. Genetic susceptibility to tobacco-related cancer. Oncogene. 2004;23(38):6500–23.

    Article  CAS  PubMed  Google Scholar 

  37. Gibson GJ, Loddenkemper R, Sibille Y, Lundback B. The European lung white book: respiratory health and disease in Europe, European Respiratory Society, 01.09.2013. 224–237.

  38. Toyooka S, Matsuo K, Shigematsu H, Kosaka T, Tokumo M, Yatabe Y, et al. The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer. Clin Cancer Res. 2007;13(19):5763–8.

    Article  CAS  PubMed  Google Scholar 

  39. Hecht SS. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol. 2002;3(8):461–9.

    Article  CAS  PubMed  Google Scholar 

  40. Hecht SS. DNA adduct formation from tobacco-specific N-nitrosamines. Mutat Res. 1999;424(1–2):127–42.

    Article  CAS  PubMed  Google Scholar 

  41. Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91(14):1194–210.

    Article  CAS  PubMed  Google Scholar 

  42. Liu W, He L, Ramirez J, et al. Functional EGFR germline polymorphisms may confer risk for EGFR somatic mutations in non-small cell lung cancer, with a predominant effect on exon 19 microdeletions. Cancer Res. 2011;71(7):2423–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tsao AS, Tang XM, Sabloff B, Xiao L, Shigematsu H, Roth J, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol. 2006;1:231–9.

    Article  PubMed  Google Scholar 

  44. Zhou W, Christiani DC. East meets west: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians. Chin J Cancer. 2011;30(5):287–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. John T, Liu G, Tsao MS. Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. Oncogene. 2009;28(1):S14–23.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was financially supported by the Ministry of Science, Republic of Serbia, 175056.

Author information

Authors and Affiliations

  1. Institute of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovica 12, 34000, Kragujevac, Serbia

    Jasmina Obradović

  2. Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000, Kragujevac, Serbia

    Natasa Djordjević & Vladimir Jurišić

  3. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11010, Belgrade, Serbia

    Natasa Tošic, Biljana Stanković & Sonja Pavlović

  4. Institute for Oncology of Vojvodina, Put Doktora Goldmana 4, 21204, Sremska Kamenica, Serbia

    Jasminka Mrdjanović

  5. Institute for Pulmonary Diseases of Vojvodina, Clinic for Pulmonary Oncology, Faculty of Medicine, University of Novi Sad, Put Doktora Goldmana 4, 21204, Sremska Kamenica, Serbia

    Jelena Stanić, Bojan Zarić & Branislav Perin

Authors
  1. Jasmina Obradović
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natasa Djordjević
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natasa Tošic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasminka Mrdjanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Biljana Stanković
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jelena Stanić
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bojan Zarić
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Branislav Perin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sonja Pavlović
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vladimir Jurišić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vladimir Jurišić.

Ethics declarations

Conflict of interests

None

Ethical standards

The study was approved by local ethics committees.

Informed consent

Written informed consent was obtained from all study subjects.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Obradović, J., Djordjević, N., Tošic, N. et al. Frequencies of EGFR single nucleotide polymorphisms in non-small cell lung cancer patients and healthy individuals in the Republic of Serbia: a preliminary study. Tumor Biol. 37, 10479–10486 (2016). https://doi.org/10.1007/s13277-016-4930-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-4930-4

Keywords

Search

Navigation