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Epidermal growth factor receptor mutations in East European non-small cell lung cancer patients

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Abstract

Background

Epidermal growth factor receptor (EGFR) gene mutations are recurrently observed in non-small cell lung carcinomas (NSCLCs), and it has been found that they may serve as specific therapeutic targets. The aim of the present study was to determine the prevalence of EGFR gene mutations in NSCLCs in an East European (Bulgarian) population in different histological subtypes, in cytological versus histological samples and in primary versus metastatic lesions.

Methods

In this study 1427 NSCLC samples were included. DNA was extracted from either formalin-fixed paraffin embedded (FFPE) tissues or cytology specimens and analyzed for the presence of 29 recurrent EGFR gene mutations using SARMS PCR.

Results

EGFR gene mutations were found to occur significantly more often in female than in male patients (19.4 % vs. 5.4 %; p < 0.001), in adenocarcinomas than in squamous cell carcinomas or other histological subtypes (12.5 % vs. 6.2 %, and 7.6 %, respectively; p = 0.009), and in never smokers than in ex-smokers and current smokers (22.9 % vs. 8.5 % and 4.9 %, respectively; p < 0.001). No significant differences were observed in the occurrence of EGFR gene mutations in primary tumors compared to metastases (7.9 % vs. 11.2 %; p = 0.092), or in FFPE samples compared to cytological samples (8.9 % vs. 8.1 %; p = 0.813).

Conclusions

Our data show that the overall frequency of EGFR gene mutations in lung adenocarcinomas in the East European cohort studied is within the range of that observed in North American and West European populations, but that its frequency in squamous cell carcinomas is higher than that in any population reported to date. All specimens appeared to be suitable for EGFR gene mutation analysis, irrespective nature or origin.

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References

  1. GLOBOCAN 2008 (IARC) Section of Cancer Information, http://globocan.iarc.fr/. Accessed 21 Sep 2013

  2. A. Koren, H. Motaln, T. Cufer, Lung cancer stem cells: a biological and clinical perspective. Cell. Oncol. 36, 265 (2013)

  3. P. Boyle, B. Levin, WHO/IARC World Cancer Report 2008 (International Agency for Cancer Research Press, Lyon, 2008)

    Google Scholar 

  4. J.R. Molina, P. Yang, S.D. Cassivi, S.E. Schild, A.A. Adjei, Non–small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 83, 584 (2008)

    Article  PubMed Central  PubMed  Google Scholar 

  5. Y. Miyamae, K. Shimizu, J. Hirato, T. Araki, K. Tanaka, H. Ogawa, S. Kakegawa, M. Sugano, T. Nakano, Y. Mitani, K. Kaira, I. Takeyoshi, Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. Oncol Rep. 25, 921 (2011)

    CAS  PubMed  Google Scholar 

  6. N. Peled, M.W. Wynes, N. Ikeda, T. Ohira, K. Yoshida, J. Qian, M. Ilouze, R. Brenner, Y. Kato, C. Mascaux, F.R. Hirsch, Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. Cell. Oncol. 36, 277 (2013)

  7. S.H. Ahn, E.H. Jeong, T.G. Lee, S.Y. Kim, H.R. Kim, C.H. Kim, Gefitinib induces cytoplasmic translocation of the CDK inhibitor p27 and its binding to a cleaved intermediate of caspase 8 in non-small cell lung cancer cells. Cell. Oncol. 37, 377 (2014)

    Article  CAS  Google Scholar 

  8. W.D. Travis, E. Brambilla, H.K. Muller-Hemerlink, C.C. Harris, World Health Organization classification of tumors. Pathology and genetics of tumours of the lung, pleura, thymus and heart (IARC Press, Lyon, 2004)

    Google Scholar 

  9. N. Dimitrova, M. Vukov, Z. Valerianova, Cancer Incidence in Bulgaria 2009 (AVIS-24 Ltd, Sofia, 2011)

    Google Scholar 

  10. T.S. Mok, Y.L. Wu, S. Thongprasert, C.H. Yang, D.T. Chu, N. Saijo, P. Sunpaweravong, B. Han, B. Margono, Y. Ichinose, Y. Nishiwaki, Y. Ohe, J.J. Yang, B. Chewaskulyong, H. Jiang, E.L. Duffield, C.L. Watkins, A.A. Armour, M. Fukuoka, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. New Engl. J. Med. 361, 947 (2009)

    Article  CAS  PubMed  Google Scholar 

  11. C. Willmore-Payne, J.A. Holden, C.T. Wittwer, L.J. Layfield, The use of EGFR exon 19 and 21 unlabeled DNA probes to screen for activating mutations in non–small cell lung. J. Biomol. Tech. 19, 217 (2008)

    PubMed Central  PubMed  Google Scholar 

  12. T.J. Lynch, D.W. Bell, R. Sordella, S. Gurubhagavatula, R.A. Okimoto, B.W. Brannigan, P.L. Harris, S.M. Haserlat, J.G. Supko, F.G. Haluska, D.N. Louis, D.C. Christiani, J. Settleman, D.A. Haber, Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Engl. J. Med. 350, 2129 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. J.G. Paez, P.A. Jänne, J.C. Lee, S. Tracy, H. Greulich, S. Gabriel, P. Herman, F.J. Kaye, N. Lindeman, T.J. Boggon, K. Naoki, H. Sasaki, Y. Fujii, M.J. Eck, W.R. Sellers, B.E. Johnson, M. Meyerson, EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304, 1497 (2004)

    Article  CAS  PubMed  Google Scholar 

  14. W. Pao, V. Miller, M. Zakowski, J. Doherty, K. Politi, I. Sarkaria, B. Singh, R. Heelan, V. Rusch, L. Fulton, E. Mardis, D. Kupfer, R. Wilson, M. Kris, H. Varmus, 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. 101, 13306 (2004)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. T. Takano, Y. Ohe, H. Sakamoto, K. Tsuta, Y. Matsuno, U. Tateishi, S. Yamamoto, H. Nokihara, N. Yamamoto, I. Sekine, H. Kunitoh, T. Shibata, T. Sakiyama, T. Yoshida, T. Tamura, EGFR mutations and gene amplification in NSCLC: molecular analysis of the IDEAL/INTACT Gefitinib trials. J. Clin. Oncol. 23, 6829 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. B. Gao, Y. Sun, J. Zhang, Y. Ren, R. Fang, X. Han, L. Shen, X.Y. Liu, W. Pao, H. Chen, H. Ji, Spectrum of LKB1, EGFR, and KRAS mutations in Chinese lung adenocarcinomas. J. Thorac. Oncol. 5, 1130 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  17. A. Marchetti, C. Martella, L. Felicioni, F. Barassi, S. Salvatore, A. Chella, P.P. Camplese, T. Iarussi, F. Mucilli, A. Mezzetti, F. Cuccurullo, R. Sacco, F. Buttitta, EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J. Clin. Oncol. 23, 857 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. R.K. Hsieh, K.H. Lim, H.T. Kuo, C.Y. Tzen, M.J. Huang, Female sex and bronchioloalveolar pathologic subtype predict EGFR mutations in non-small cell lung cancer. Chest. 128, 317 (2005)

    Article  CAS  PubMed  Google Scholar 

  19. A.J. Smits, J.A. Kummer, J.W. Hinrichs, G.J. Herder, K.C. Scheidel-Jacobse, N.M. Jiwa, P.T. Nooijen, M.G. Looijen-Salamon, M.J. Ligtenberg, F.B. Thunnissen, D.A. Heideman, R.A. de Weger, A. Vink, EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma. Cell. Oncol. 35, 189 (2012)

  20. A.M. Cushman-Vokoun, A.M. Crowley, S.A. Rapp, T.C. Greiner, Comparison study of the performance of the QIAGEN EGFR RGQ and EGFR Pyro assays for mutation analysis in non-small cell lung cancer. Am. J. Clin. Pathol. 140, 7 (2013)

    Article  PubMed  Google Scholar 

  21. N.C. Bae, M.H. Chae, M.H. Lee, K.M. Kim, E.B. Lee, C.H. Kim, T.I. Park, S.B. Han, S. Jheon, T.H. Jung, J.Y. Park, EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients. Cancer Genet. Cytogenet. 173, 107 (2007)

    Article  CAS  PubMed  Google Scholar 

  22. R. Rosell, T. Moran, C. Queralt, R. Porta, F. Cardenal, C. Camps, M. Majem, G. Lopez-Vivanco, D. Isla, M. Provencio, A. Insa, B. Massuti, J.L. Gonzalez-Larriba, L. Paz-Ares, I. Bover, R. Garcia-Campelo, M.A. Moreno, S. Catot, C. Rolfo, N. Reguart, R. Palmero, J.M. Sánchez, R. Bastus, C. Mayo, J. Bertran-Alamillo, M.A. Molina, J.J. Sanchez, M. Taron, Spanish Lung Cancer Group, Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958 (2009)

    Article  CAS  PubMed  Google Scholar 

  23. S. Dearden, J. Stevens, Y.-L. Wu, D. Blowers, Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann. Oncol. 24, 2371 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. J.L. Marks, M.D. McLellan, M.F. Zakowski, A.E. Lash, Y. Kasai, S. Broderick, I.S. Sarkaria, D. Pham, B. Singh, T.L. Miner, G.A. Fewell, L.L. Fulton, E.R. Mardis, R.K. Wilson, M.G. Kris, V.W. Rusch, H. Varmus, W. Pao, Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. PLoS One. 2, e426 (2007)

    Article  PubMed Central  PubMed  Google Scholar 

  25. G.J. Riely, K.A. Politi, V.A. Miller, W. Pao, Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin. Cancer Res. 12, 7232 (2006)

    Article  CAS  PubMed  Google Scholar 

  26. H. Cortes-Funes, C. Gomez, R. Rosell, P. Valero, C. Garcia-Giron, A. Velasco, A. Izquierdo, P. Diz, C. Camps, D. Castellanos, V. Alberola, F. Cardenal, J.L. Gonzalez-Larriba, J.M. Vieitez, I. Maeztu, J.J. Sanchez, C. Queralt, C. Mayo, P. Mendez, T. Moran, M. Taron, Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Annals of Oncology. 16, 1081 (2005)

  27. T. Kosaka, Y. Yatabe, H. Endoh, H. Kuwano, T. Takahashi, T. Mitsudomi, Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 64, 8919 (2004)

    Article  CAS  PubMed  Google Scholar 

  28. Y.H. Soung, J.W. Lee, S.Y. Kim, S.H. Seo, W.S. Park, S.W. Nam, S.Y. Song, J.H. Han, C.K. Park, J.Y. Lee, N.J. Yoo, S.H. Lee, Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch. 446, 483 (2005)

    Article  CAS  PubMed  Google Scholar 

  29. K. Sugio, H. Uramoto, K. Ono, T. Oyama, T. Hanagiri, M. Sugaya, Y. Ichiki, T. So, S. Nakata, M. Morita, K. Yasumoto, 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 (2006)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Y. Tomizawa, H. Iijima, N. Sunaga, K. Sato, A. Takise, Y. Otani, S. Tanaka, T. Suga, R. Saito, T. Ishizuka, K. Dobashi, J.D. Minna, T. Nakajima, M. Mori, Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer. Clin. Cancer Res. 11, 6816 (2005)

    Article  CAS  PubMed  Google Scholar 

  31. S.F. Huang, H.P. Liu, L.H. Li, Y.C. Ku, Y.N. Fu, H.Y. Tsai, Y.T. Chen, Y.F. Lin, W.C. Chang, H.P. Kuo, Y.C. Wu, Y.R. Chen, S.F. Tsai, High frequency of epidermal growth factor receptor mutations with complex patterns in nonsmall cell lung cancers related to gefitinib responsiveness in Taiwan. Clin. Cancer Res. 10, 8195 (2004)

    Article  CAS  PubMed  Google Scholar 

  32. G.J. Riely, W. Pao, D. Pham, A.R. Li, N. Rizvi, E.S. Venkatraman, M.F. Zakowski, M.G. Kris, M. Ladanyi, V.A. Miller, Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin. Cancer Res. 12, 839 (2006)

    Article  CAS  PubMed  Google Scholar 

  33. M. Majem, J. Remon, Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients. Transl. Lung Cancer Res. 2, 226 (2013)

    PubMed Central  PubMed  Google Scholar 

  34. S. Toyooka, K. Kiura, T. Mitsudomi, EGFR mutation and response of lung cancer to gefitinib. N. Engl. J. Med. 352, 2136 (2005)

    Article  CAS  PubMed  Google Scholar 

  35. S. Kobayashi, T.J. Boggon, T. Dayaram, P.A. Janne, O. Kocher, M. Meyerson, B.E. Johnson, M.J. Eck, D.G. Tenen, B. Halmos, EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786 (2005)

    Article  CAS  PubMed  Google Scholar 

  36. L. Cheng, R. Alexander, G. MacLennan, O. Cummings, R. Montironi, A. Lopez-Beltran, H. Cramer, D. Davidson, S. Zhang, Molecular pathology of lung cancer: key to personalized medicine. Mod. Pathol. 25, 347 (2012)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Radka Budinova for technical assistance with some of the samples. The authors express special thanks to all the referring physicians. Astra Zeneca has provided the kits for EGFR gene mutation testing.

Conflict of interests

DM and AS do not have any conflicts of interest. SB and YS have received honoraria from Astra Zeneca for consultancies regarding EGFR testing in Bulgaria.

Ethical standards

The authors declare that the experiments comply with the current laws of the country (Bulgaria) in which they were performed.

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Correspondence to Dora Marinova Marinova.

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Bichev, S.N., Marinova, D.M., Slavova, Y.G. et al. Epidermal growth factor receptor mutations in East European non-small cell lung cancer patients. Cell Oncol. 38, 145–153 (2015). https://doi.org/10.1007/s13402-014-0211-7

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  • DOI: https://doi.org/10.1007/s13402-014-0211-7

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