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Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas

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Abstract

Both epidermal growth factor receptor (EGFR) and RAS gene mutations contribute to the development of non-small cell lung cancer (NSCLC). Because RAS is one of the downstream molecules in the EGFR signal transduction, the association between the somatic mutations of EGFR and RAS may be important in the pathogenesis of NSCLC . However, to date, such data are lacking. In this study, we analyzed the hotspot regions of K-RAS gene (codons 12, 13, 59 and 61) and EGFR gene (exons 18, 19 and 21) in 153 NSCLC tissue samples including 69 adenocarcinomas. Overall, we detected 30 EGFR mutations (19.6%) and 6 K-RAS mutations (3.9%) in the 153 NSCLCs. In the 69 adenocarcinomas, 26 EGFR mutations (37.7%) and six K-RAS mutations (8.7%) were detected. Of note, the 26 tumors with EGFR mutations did not harbor any K-RAS mutations, and the six tumors with K-RAS mutations did not harbor any EGFR mutations. Inverse relationship between K-RAS and EGFR mutations in the lung adenocarcinoma was statistically significant (P=0.046, χ2 test). As regards smoking history, EGFR mutation was significantly associated with never-smoking history, whereas K-RAS mutation was significantly associated with smoking history. Our data suggest that mutations of EGFR and K-RAS genes might separately, but not cooperatively, contribute to lung adenocarcinoma pathogenesis, and that EGFR and K-RAS mutants could separately be anti-neoplastic targets in lung adenocarcinomas.

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Abbreviations

PCR:

polymerase chain reaction

SSCP:

single strand conformation polymorphism

EGFR:

epidermal growth factor receptor

NSCLC:

non-small cell lung cancer

BAC:

bronchioloalveolar carcinoma

References

  1. Adjei AA (2001) Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 93:1062–1074

    Google Scholar 

  2. Ahrendt SA, Decker PA, Alawi EA, Zhu YYR, Sanchez-Cespedes M, Yang SC, Haasler GB, Kajdacsy-Balla A, Demeure MJ, Sidransky D (2001) Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 92:1525–1530

    Google Scholar 

  3. Arteaga CL, Moulder SL, Yakes FM (2002) HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol 29:4–10

    Article  CAS  Google Scholar 

  4. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Google Scholar 

  5. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042

    Article  CAS  PubMed  Google Scholar 

  6. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246

    Article  PubMed  Google Scholar 

  7. Graziano SL, Gamble GP, Newman NB, Abbott LZ, Rooney M, Mookherjee S, Lamb ML, Kohman LJ, Poiesz BJ (1999) Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 17:668–675

    Google Scholar 

  8. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ, American Cancer Society (2004) Cancer statistics, 2004. Cancer J Clin 54:8–29

    PubMed  Google Scholar 

  9. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284:31–53

    Google Scholar 

  10. Kamata T, Feramisco JR (1984) Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310:147–150

    Google Scholar 

  11. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158

    Article  CAS  PubMed  Google Scholar 

  12. Lee JY, Dong SM, Kim SY, Yoo NJ, Lee SH, Park WS (1998) A simple, precise and economical microdissection technique for analysis of genomic DNA from archival tissue sections. Virchows Arch 433:305–309

    Google 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 350:2129–2139

    Article  CAS  PubMed  Google Scholar 

  14. Paez JG, Janne 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 304:1497–1500

    Article  CAS  PubMed  Google Scholar 

  15. 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 101:13306–13311

    Google Scholar 

  16. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532

    Google Scholar 

  17. Slebos RJ, Hruban RH, Dalesio O, Mooi WJ, Offerhaus GJ, Rodenhuis S (1991) Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst 83:1024–1027

    Google Scholar 

  18. Sordella R, Bell DW, Haber DA, Settleman J (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163–1167

    Google Scholar 

  19. Sridhar SS, Seymour L, Shepherd FA (2003) Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 4:397–406

    Google Scholar 

  20. Vojtek AB, Hollenberg SM, Cooper JA (1993) Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74:205–214

    Google Scholar 

  21. Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, Gibson KH (2002) ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749–5754

    Google Scholar 

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Acknowledgements

This work was supported by the Korea Science & Engineering Foundation (KOSEF) through the Cell Death Disease Research Center at The Catholic University of Korea (R13-2002-005-01004-0).

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Correspondence to Sug Hyung Lee.

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Soung, Y.H., Lee, J.W., Kim, S.Y. et al. Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch 446, 483–488 (2005). https://doi.org/10.1007/s00428-005-1254-y

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  • DOI: https://doi.org/10.1007/s00428-005-1254-y

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