Journal of Cancer Research and Clinical Oncology

, Volume 136, Issue 12, pp 1937–1944 | Cite as

Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer

  • Young Joo Lee
  • Hyo Sub Shim
  • Young Ae Kang
  • Su Jung Hong
  • Hyun Ki Kim
  • Hoguen Kim
  • Se Kyu Kim
  • Sung Ho Choi
  • Joo-Hang Kim
  • Byoung Chul ChoEmail author
Original Paper



This study aimed to determine the dose effect of smoking on the mutational frequency and spectrum of epidermal growth factor receptor (EGFR) gene in Korean non-small cell lung cancer (NSCLC).


Detailed smoking histories were obtained from 324 consecutively enrolled Korean NSCLC patients. Mutational status of EGFR (exon 18–21) was determined using nested polymerase chain reaction amplification.


A total of 108 EGFR mutations (33.3%) were identified in 107 patients. Decreased EGFR mutation rate with increased smoking dose was observed, with 48.0% (82 of 171) in never smokers, 23.1% (15 of 65) in former smokers, and 11.4% (10 of 88) in current smokers. The incidence of EGFR mutation was significantly lower in patients who smoked for more than 25 pack-years (P < 0.0001) or who stopped smoking cigarettes less than 10 years ago (P < 0.0001). Mutations in exon 19 or 21 were associated with fewer total smoke years (5.0 vs. 25.0 years in exon 20, P = 0.024), fewer total pack-years (6.3 vs. 38.9 pack-years in exon 20, P = 0.079), and more smoke-free years (11.1 vs. 3.6 years in exon 20, P = 0.027), compared with those in exon 20. Mutations in exon 19 or 21 were associated with female (P < 0.0001), never smoker (P < 0.0001), and adenocarcinoma (P < 0.0001), whereas those in exon 20 were not.


Smoking dosage affects the incidence of EGFR mutations. EGFR mutations in exon 19 or 21 are associated with low exposure to cigarette smoke, whereas EGFR mutation in exon 20 is more common in smokers.


Non-small cell lung cancer Smoking Epidermal growth factor receptor (EGFR) Mutation 



This study was supported by a faculty research grant of Yonsei University College of Medicine for 6-2009-0066. We thank the members of Lung Cancer Clinic Severance Hospital for thoughtful discussion and review of the manuscript.

Conflict of interest statement

None declared.


  1. Castillo L, Etienne-Grimaldi MC, Fischel JL, Formento P, Magn N, Milano G (2004) Pharmacological background of EGFR targeting. Ann Oncol 15:1007–1012CrossRefPubMedGoogle Scholar
  2. Chou T, Chiu C, Li L, Hsiao C, Tzen C, Chang K, Chen Y, Perng R, Tsai S, Tsai C (2005) Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 11:3750–3757CrossRefPubMedGoogle Scholar
  3. Gazdar AF, Shigematsu H, Herz J, Minna JD (2004) Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers? Trends Mol Med 10:481–486CrossRefPubMedGoogle Scholar
  4. Greulich H, Chen T, Feng W, Jnne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313–e313CrossRefPubMedGoogle Scholar
  5. Huang SF, Liu HP, Li LH, Ku YC, Fu YN, Tsai HY, Chen YT, Lin YF, Chang WC, Kuo HP, Wu YC, Chen YR, Tsai SF (2004) High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 10:8195–8203CrossRefPubMedGoogle Scholar
  6. Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, Suehisa H, Ouchida M, Aoe K, Aoe M, Kiura K, Shimizu N, Date H (2006) Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 66:7854–7858CrossRefPubMedGoogle Scholar
  7. Kang SM, Kang HJ, Shin JH, Kim H, Shin DH, Kim SK, Kim JH, Chung KY, Kim SK, Chang J (2007) Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer 109:581–587CrossRefPubMedGoogle Scholar
  8. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu Y, Li L, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao M, Osterlind K, Reck M, Armour A, Shepherd FA, Lippman SM, Douillard J (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818CrossRefPubMedGoogle Scholar
  9. Kobayashi S, Boggon TJ, Dayaram T, Jnne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792CrossRefPubMedGoogle Scholar
  10. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64:8919–8923CrossRefPubMedGoogle Scholar
  11. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670CrossRefPubMedGoogle Scholar
  12. Le Calvez F, Mukeria A, Hunt JD, Kelm O, Hung RJ, Tanire P, Brennan P, Boffetta P, Zaridze DG, Hainaut P (2005) TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 65:5076–5083CrossRefPubMedGoogle Scholar
  13. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139CrossRefPubMedGoogle Scholar
  14. Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, Hatooka S, Shinoda M, Takahashi T, Yatabe Y (2005) Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23:2513–2520CrossRefPubMedGoogle Scholar
  15. Mok TS, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang J, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour A, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957CrossRefPubMedGoogle Scholar
  16. Mulloy R, Ferrand A, Kim Y, Sordella R, Bell DW, Haber DA, Anderson KS, Settleman J (2007) Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Cancer Res 67:2325–2330CrossRefPubMedGoogle Scholar
  17. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500CrossRefPubMedGoogle Scholar
  18. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311CrossRefPubMedGoogle Scholar
  19. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73–e73CrossRefPubMedGoogle Scholar
  20. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMedGoogle Scholar
  21. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht S, Hainaut P (2002) Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21:7435–7451CrossRefPubMedGoogle Scholar
  22. Pham D, Kris MG, Riely GJ, Sarkaria IS, McDonough T, Chuai S, Venkatraman ES, Miller VA, Ladanyi M, Pao W, Wilson RK, Singh B, Rusch VW (2006) Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 24:1700–1704CrossRefPubMedGoogle Scholar
  23. Rami-Porta R, Crowley J, Goldstraw P (2009) The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 15:4–9PubMedGoogle Scholar
  24. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181CrossRefPubMedGoogle Scholar
  25. Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabrbara P, Seymour L (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMedGoogle Scholar
  26. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339–346CrossRefPubMedGoogle Scholar
  27. Sugio K, Uramoto H, Ono K, Oyama T, Hanagiri T, Sugaya M, Ichiki Y, So T, Nakata S, Morita M, Yasumoto K (2006) Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer 94:896–903CrossRefPubMedGoogle Scholar
  28. Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, Ichimura K, Tsuda T, Yano M, Tsukuda K, Tabata M, Ueoka H, Tanimoto M, Date H, Gazdar AF, Shimizu N (2005) The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 11:1167–1173PubMedGoogle Scholar
  29. Travis W, Colby T, Corrin B, Shimosato Y, Brambilla E (1999) Histological typing of lung and pleural tumours, 3rd edn. Springer, Berlin, pp 28–40Google Scholar
  30. Tsao M, Sakurada A, Cutz J, Zhu C, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353:133–144CrossRefPubMedGoogle Scholar
  31. Wynder EL, Graham EA (1985) Landmark article May 27, 1950: tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. A study of six hundred and eighty-four proved cases. By Ernest L. Wynder and Evarts A. Graham. JAMA 253:2986–2994CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Young Joo Lee
    • 1
  • Hyo Sub Shim
    • 3
  • Young Ae Kang
    • 4
  • Su Jung Hong
    • 2
  • Hyun Ki Kim
    • 3
  • Hoguen Kim
    • 3
  • Se Kyu Kim
    • 4
  • Sung Ho Choi
    • 5
  • Joo-Hang Kim
    • 2
  • Byoung Chul Cho
    • 2
    Email author
  1. 1.Center for Clinical TrialNational Cancer CenterGyeonggiRepublic of Korea
  2. 2.Yonsei Cancer Center, Division of Medical Oncology, Department of Internal MedicineYonsei University College of MedicineSeodaemun-gu, SeoulRepublic of Korea
  3. 3.Department of PathologyYonsei University College of MedicineSeoulRepublic of Korea
  4. 4.Department of Internal MedicineYonsei University College of MedicineSeoulRepublic of Korea
  5. 5.ISU ABXIS CO., LTD.SeoulRepublic of Korea

Personalised recommendations