Abstract
Introduction
Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC). However, EGFR mutations status at C-terminal domain has not been reported in detail.
Materials and methods
We investigated the EGFR mutation and polymorphism statuses at C-terminal domain in 398 surgically treated NSCLC cases. Two hundred and sixty-eight adenocarcinoma cases were included. The presence or absence of EGFR mutation and polymorphism was analyzed by direct sequences.
Results
A novel EGFR somatic mutation at exon 25 (G3034, D1012H) was found from 1 of 398 lung cancer patients. During sequencing of EGFR C-terminal domain in NSCLC, 194 EGFR polymorphism (C2982T) cases were identified at exon 25. The polymorphism statuses were not correlated with gender, smoking status (never smoker vs. smoker), pathological subtypes and EGFR mutations. The EGFR polymorphism ratio was significantly higher in younger NSCLC (≤60, 56.8%) than in older NSCLC (>60, 45.6%, P = 0.0467). The EGFR polymorphism ratio was significantly higher in lymph node positive NSCLC (57.4%) than in lymph node negative NSCLC (44%, P = 0.0168). In 46 total gefitinib treated NSCLC patients, exon 25 polymorphism was not correlated with prognosis.
Conclusion
EGFR mutation at C-terminal in lung cancers seemed to be extremely rare, however, this D1012H mutation might be a role in EGFR function. EGFR polymorphism at exon 25 might be correlated with progression of NSCLC.
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References
Bertics PJ, Gill GN (1985) Self-phospholylation enhances the protein-tyrosine kinase activity of the epidermal growth factor receptor. J Biol Chem 260:14642–14647
Bertics PJ, Chen WS, Hubler L, Lazar CS, Rosenfeld MG, Gill GN (1988) Alteration of epidermal growth factor receptor activity by mutation of its primary carboxyl-terminal site of tyrosine self-phosphorylation. J Biol Chem 263:3610–3617
Cheng K, Koland JG (1996) Nucleotide binding by the epidermal growth factor receptor protein-tyrosine kinase. Trinitrophenyl-ATP as a spectroscopic probe. J Biol Chem 271:311–318
Endo K, Konishi A, Sasaki H, Takada M, Tanaka H, Okumura M, Kawahara M, Sugiura H, Kuwabara Y, Fukai I, Matsumura A, Yano M, Kobayashi Y, Mizuno K, Haneda H, Suzuki E, Iuchi K, Fujii Y (2005) Epidermal growth factor receptor gene mutation in non-small cell lung cancer using highly sensitive and fast TaqMan PCR assay. Lung Cancer 50:375–384
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, Feyereuslova 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
Fukushima T, Favereaux F, Huang H, Shimizu T, Yonekawa Y, Nakazato Y, Ohagki H (2006) Genetic alterations in primary glioblastomas in Japan. J Neuropathol Exp Neurol 65:12–18
Ginsberg RJ, Kris K, Armstrong G (1993) Cancer of the lung. In: Principles and practice of oncology, 4th edn. Lippincott, Philadelphia, pp 673–682
Kang D, Gridley G, Huang WY, Engel LS, Winn DM, Brown LM, Bravo-Otero E, Wu T, Diehl SR, Hayes RB (2005) Microsatellite polymorphisms in the epidermal growth factor receptor (EGFR) gene and the transforming growth factor-alpha (TGFA) gene and risk of oral cancer in Puerto Rico. Pharmacogenet Genomics 15:343–347
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 64:8919–8923
Kris MG, Natale RB, Herbst RS, Lynch TJ, 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: randomized trial. JAMA 290:2149–2158
Landau M, Fleishman SJ, Ben-Tal N (2004) A putative mechanism for downregulation of the catalytic activity of the EGF receptor via direct contact between its kinase and C-terminal domains. Structure 12:2265–2275
Lee NY, Hazlett TL, Koland JG (2006) Structure and dynamics of the epidermal growth factor receptor C-terminal phopshorylation domain. Protein Sci 15:1142–1152
Liu G, Gurubhagavatula S, Zhou W, Wang Z, Yeap BY, Asomaning K, Su L, Heist R, Lynch TJ, Christiani DC (2008) Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. Pharmacogenomics J 8:129–138
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Branniga 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. New Engl J Med 350:2129–2139
Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, Camplese PP, Iarussi T, Muchilli F, Mezzetti A, Cuccurullo F, Sacco R, Buttitta F (2005) 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 Onlol 23:857–865
Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, Krug LM, Pao W, Rizvi N, Pizzo B, Tyson L, Venkatraman E, Ben-Porat L, Memoli N, Zakowski M, Rusch V, Heelan RT (2004) Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103–1109
Nicolson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37:S9–S15
Onn A, Correa AM, Gilcrease M, Isobe T, Massarelli E, Bucane CD, O’Reilly MS, Hong WK, Fidler IJ, Putnum JB, Herbst RS (2004) Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer. Clin Cancer Res 10:136–143
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, Seller WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkari I, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kri 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 elrotinib. Proc Natl Acad Sci USA 101:13306–13311
Sasaki H, Endo K, Konishi A, Takada M, Kawahara M, Iuchi K, Matsumura A, Okumura M, Tanaka H, Kawaguchi T, Shimizu T, Takeuchi H, Yano M, Fukai I, Fujii Y (2005) EGFR mutation status in Japanese lung cancer patients: genotyping analysis using LighyCycler. Clin Cancer Res 11:2924–2929
Sasaki H, Shimizu S, Endo K, Takada M, Kawahara M, Tanaka H, Matsumura A, Iuchi K, Haneda H, Suzuki E, Kobayashi Y, Yano M, Fujii Y (2006) EGFR and erbB2 mutation status in Japanese lung cancer patients. Int J Cancer 118:180–184
Shigematsu H, Lin L, Takahashi T, Numura 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 mutation in lung cancers. J Natl Cancer Inst 97:339–346
Shintani S, Matsuo K, Crohin CC, McBride J, Tsuji T, Donoff RB, Posner M, Todd R, Wong DT (1999) Intragenic mutation analysis of the human epidermal growth factor receptor (EGFR) gene in malignant human oral keratinocytes. Cancer Res 59:4142–4147
Thatcher N, Chang A, Purvish P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Tan EH, Pemberton K, Archer V, Carroll K (2005) Gefitinib plus best supportive care in previously treated patients with refractory advance non-small-cell lung cancer: result from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537
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, Gazder AF, Shimizu N (2005) The relationship between epidermal growth factor receptor mutation and clinicopathological feature in non-small cell lung cancers. Clin Cancer Res 11:1167–1173
Zhang W, Stabile LP, Keohavong P, Romkes M, Grandis JR, Traynor A, Siegfried JM (2006) Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. J Thorac Oncol 1:635–646
Wang Q, Zhu F, Wang Z (2007) Identification of EGF receptor C-terminal sequence 1005–1017 and di-leucine motif (1010) LL(1011) as essential in EGF receptor endocytosis. Exp Cell Res 313:3349–3363
Acknowledgments
The authors would like to thank Mrs. Emi Sugiyama for his excellent technical assistances. This work was supported by AstraZeneca Research Grant 2004, Grand-in-Aid for Research in Nagoya City University (2006), and Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science (JSPS) (Nos. 19390367, 18390381, 18659407).
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Sasaki, H., Okuda, K., Takada, M. et al. A novel EGFR mutation D1012H and polymorphism at exon 25 in Japanese lung cancer. J Cancer Res Clin Oncol 134, 1371–1376 (2008). https://doi.org/10.1007/s00432-008-0411-5
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DOI: https://doi.org/10.1007/s00432-008-0411-5