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Published in: Journal of Cancer Research and Clinical Oncology 8/2011

Open Access 01-08-2011 | Original Paper

Molecular profiles of EGFR, K-ras, c-met, and FGFR in pulmonary pleomorphic carcinoma, a rare lung malignancy

Authors: Soohyeon Lee, Youngwook Kim, Jong-Mu Sun, Yoon La Choi, Jhin Gook Kim, Young-Mog Shim, Yeon Hee Park, Jin Seok Ahn, Keunchil Park, Jung Ho Han, Myung-Ju Ahn

Published in: Journal of Cancer Research and Clinical Oncology | Issue 8/2011

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Abstract

Background

Pulmonary pleomorphic carcinoma (PPC) is a rare type of lung cancer characterized by the poor response to conventional chemotherapy and subsequent disappointing outcomes. Therefore, it is paramount to delineate the molecular characteristics of this disease entity.

Methods

In this study, we retrospectively examined the surgical specimens of 61 patients who underwent lung surgery. Mutational or gene amplification statuses of epidermal growth factor receptor (EGFR), k-ras, c-kit, c-met, and fibroblast growth factor receptor (FGFR) were examined using genomic DNA sequencing, real-time PCR and/or fluorescence in situ hybridization (FISH).

Results

The median age was 61 years, and 50 patients were men and 11 were women. In the histologic review of epithelial component, adenocarcinoma were in 44 cases (72%), squamous cell carcinoma in 15 (25%) and large cell carcinoma in 2 patients (3%). Overall, 30 cases (49%) had any molecular alterations. Nine patients (15%) possessed EGFR deletion in exon 19 (n = 8) or L858R mutations in exon 21 (n = 1), while 3 other cases having atypical EGFR mutations. Six patients (9.8%) had k-ras mutations in exon 12, and 3 had c-kit mutations. High gene copy number of c-met was found in 11 patients (18.0%) and that of FGFR was in 6 patients (9.8%). No significant relationships were identified among the occurrence and type of mutations and patient survival or any other clinicopathological variables.

Conclusions

Given the diverse repertoire of mutational profiles observed in PPC samples, clinical trials based on accurate cancer-genotyping should be considered as a legitimate treatment scheme for this rare disease entity in the future.
Literature
go back to reference Ahn MJ, Park BB, Ahn JS, Kim SW, Kim HT, Lee JS, Kang JH, Cho JY, Song HS, Park SH, Sohn CH, Shin SW, Choi JH, Ki CS, Park CK, Holmes AJ, Janne PA, Park K (2008) Are there any ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung cancer? Clin Cancer Res 14:3860–3866PubMedCrossRef Ahn MJ, Park BB, Ahn JS, Kim SW, Kim HT, Lee JS, Kang JH, Cho JY, Song HS, Park SH, Sohn CH, Shin SW, Choi JH, Ki CS, Park CK, Holmes AJ, Janne PA, Park K (2008) Are there any ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung cancer? Clin Cancer Res 14:3860–3866PubMedCrossRef
go back to reference Arita N, Mikami Y, Yoshida M, Konishi I, Horiike N, Miyauchi K, Miyazaki T, Nose M, Ono M (2005) Pleomorphic carcinoma of the lung associated with loss of heterozygosity of p53 gene. Tohoku J Exp Med 206:181–185PubMedCrossRef Arita N, Mikami Y, Yoshida M, Konishi I, Horiike N, Miyauchi K, Miyazaki T, Nose M, Ono M (2005) Pleomorphic carcinoma of the lung associated with loss of heterozygosity of p53 gene. Tohoku J Exp Med 206:181–185PubMedCrossRef
go back to reference Bae HM, Min HS, Lee SH, Kim DW, Chung DH, Lee JS, Kim YW, Heo DS (2007) Palliative chemotherapy for pulmonary pleomorphic carcinoma. Lung Cancer 58:112–115PubMedCrossRef Bae HM, Min HS, Lee SH, Kim DW, Chung DH, Lee JS, Kim YW, Heo DS (2007) Palliative chemotherapy for pulmonary pleomorphic carcinoma. Lung Cancer 58:112–115PubMedCrossRef
go back to reference Beasley MB, Brambilla E, Travis WD (2005) The 2004 world health organization classification of lung tumors. Semin Roentgenol 40:90–97PubMedCrossRef Beasley MB, Brambilla E, Travis WD (2005) The 2004 world health organization classification of lung tumors. Semin Roentgenol 40:90–97PubMedCrossRef
go back to reference Blaukovitsch M, Halbwedl I, Kothmaier H, Gogg-Kammerer M, Popper HH (2006) Sarcomatoid carcinomas of the lung–are these histogenetically heterogeneous tumors? Virchows Arch 449:455–461PubMedCrossRef Blaukovitsch M, Halbwedl I, Kothmaier H, Gogg-Kammerer M, Popper HH (2006) Sarcomatoid carcinomas of the lung–are these histogenetically heterogeneous tumors? Virchows Arch 449:455–461PubMedCrossRef
go back to reference Chang YL, Lee YC, Shih JY, Wu CT (2001) Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma. Lung Cancer 34:91–97PubMedCrossRef Chang YL, Lee YC, Shih JY, Wu CT (2001) Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma. Lung Cancer 34:91–97PubMedCrossRef
go back to reference Fischer H, Taylor N, Allerstorfer S, Grusch M, Sonvilla G, Holzmann K, Setinek U, Elbling L, Cantonati H, Grasl-Kraupp B, Gauglhofer C, Marian B, Micksche M, Berger W (2008) Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol Cancer Ther 7:3408–3419PubMedCrossRef Fischer H, Taylor N, Allerstorfer S, Grusch M, Sonvilla G, Holzmann K, Setinek U, Elbling L, Cantonati H, Grasl-Kraupp B, Gauglhofer C, Marian B, Micksche M, Berger W (2008) Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol Cancer Ther 7:3408–3419PubMedCrossRef
go back to reference Fishback NF, Travis WD, Moran CA, Guinee DG Jr, McCarthy WF, Koss MN (1994) Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases. Cancer 73:2936–2945PubMedCrossRef Fishback NF, Travis WD, Moran CA, Guinee DG Jr, McCarthy WF, Koss MN (1994) Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases. Cancer 73:2936–2945PubMedCrossRef
go back to reference Han SW, Kim TY, Jeon YK, Hwang PG, Im SA, Lee KH, Kim JH, Kim DW, Heo DS, Kim NK, Chung DH, Bang YJ (2006) Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 12:2538–2544PubMedCrossRef Han SW, Kim TY, Jeon YK, Hwang PG, Im SA, Lee KH, Kim JH, Kim DW, Heo DS, Kim NK, Chung DH, Bang YJ (2006) Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 12:2538–2544PubMedCrossRef
go back to reference Heinrich MC, Blanke CD, Druker BJ, Corless CL (2002) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703PubMedCrossRef Heinrich MC, Blanke CD, Druker BJ, Corless CL (2002) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703PubMedCrossRef
go back to reference Hong JY, Choi MK, Uhm JE, Park MJ, Lee J, Park YH, Ahn JS, Park K, Han JH, Ahn MJ (2009) The role of palliative chemotherapy for advanced pulmonary pleomorphic carcinoma. Med Oncol 26:287–291PubMedCrossRef Hong JY, Choi MK, Uhm JE, Park MJ, Lee J, Park YH, Ahn JS, Park K, Han JH, Ahn MJ (2009) The role of palliative chemotherapy for advanced pulmonary pleomorphic carcinoma. Med Oncol 26:287–291PubMedCrossRef
go back to reference Italiano A, Cortot AB, Ilie M, Martel-Planche G, Fabas T, Pop D, Mouroux J, Hofman V, Hofman P, Pedeutour F (2009) EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy. Int J Cancer 125:2479–2482PubMedCrossRef Italiano A, Cortot AB, Ilie M, Martel-Planche G, Fabas T, Pop D, Mouroux J, Hofman V, Hofman P, Pedeutour F (2009) EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy. Int J Cancer 125:2479–2482PubMedCrossRef
go back to reference Ito K, Oizumi S, Fukumoto S, Harada M, Ishida T, Fujita Y, Harada T, Kojima T, Yokouchi H, Nishimura M (2010) Clinical characteristics of pleomorphic carcinoma of the lung. Lung Cancer 68:204–210PubMedCrossRef Ito K, Oizumi S, Fukumoto S, Harada M, Ishida T, Fujita Y, Harada T, Kojima T, Yokouchi H, Nishimura M (2010) Clinical characteristics of pleomorphic carcinoma of the lung. Lung Cancer 68:204–210PubMedCrossRef
go back to reference Jagadeeswaran R, Jagadeeswaran S, Bindokas VP, Salgia R (2007) Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells. Am J Physiol Lung Cell Mol Physiol 292:L1488–L1494. doi:10.1152/ajplung.00147.2006 PubMedCrossRef Jagadeeswaran R, Jagadeeswaran S, Bindokas VP, Salgia R (2007) Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells. Am J Physiol Lung Cell Mol Physiol 292:L1488–L1494. doi:10.​1152/​ajplung.​00147.​2006 PubMedCrossRef
go back to reference Kaira K, Horie Y, Ayabe E, Murakami H, Takahashi T, Tsuya A, Nakamura Y, Naito T, Endo M, Kondo H, Nakajima T, Yamamoto N (2010) Pulmonary pleomorphic carcinoma: a clinicopathological study including EGFR mutation analysis. J Thorac Oncol 5:460–465PubMedCrossRef Kaira K, Horie Y, Ayabe E, Murakami H, Takahashi T, Tsuya A, Nakamura Y, Naito T, Endo M, Kondo H, Nakajima T, Yamamoto N (2010) Pulmonary pleomorphic carcinoma: a clinicopathological study including EGFR mutation analysis. J Thorac Oncol 5:460–465PubMedCrossRef
go back to reference Kubo T, Yamamoto H, Lockwood WW, Valencia I, Soh J, Peyton M, Jida M, Otani H, Fujii T, Ouchida M, Takigawa N, Kiura K, Shimizu K, Date H, Minna JD, Varella-Garcia M, Lam WL, Gazdar AF, Toyooka S (2009) MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. Int J Cancer 124:1778–1784PubMedCrossRef Kubo T, Yamamoto H, Lockwood WW, Valencia I, Soh J, Peyton M, Jida M, Otani H, Fujii T, Ouchida M, Takigawa N, Kiura K, Shimizu K, Date H, Minna JD, Varella-Garcia M, Lam WL, Gazdar AF, Toyooka S (2009) MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. Int J Cancer 124:1778–1784PubMedCrossRef
go back to reference Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, Johnson BE, Salgia R (2003) c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 63:6272–6281PubMed Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, Johnson BE, Salgia R (2003) c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 63:6272–6281PubMed
go back to reference Maulik G, Kijima T, Ma PC, Ghosh SK, Lin J, Shapiro GI, Schaefer E, Tibaldi E, Johnson BE, Salgia R (2002) Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 8:620–627PubMed Maulik G, Kijima T, Ma PC, Ghosh SK, Lin J, Shapiro GI, Schaefer E, Tibaldi E, Johnson BE, Salgia R (2002) Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 8:620–627PubMed
go back to reference Mochizuki T, Ishii G, Nagai K, Yoshida J, Nishimura M, Mizuno T, Yokose T, Suzuki K, Ochiai A (2008) Pleomorphic carcinoma of the lung: clinicopathologic characteristics of 70 cases. Am J Surg Pathol 32:1727–1735PubMedCrossRef Mochizuki T, Ishii G, Nagai K, Yoshida J, Nishimura M, Mizuno T, Yokose T, Suzuki K, Ochiai A (2008) Pleomorphic carcinoma of the lung: clinicopathologic characteristics of 70 cases. Am J Surg Pathol 32:1727–1735PubMedCrossRef
go back to reference Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303:1800–1805PubMedCrossRef Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303:1800–1805PubMedCrossRef
go back to reference Onitsuka T, Uramoto H, Ono K, Takenoyama M, Hanagiri T, Oyama T, Izumi H, Kohno K, Yasumoto K (2010) Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status. J Thorac Oncol 5:591–596PubMed Onitsuka T, Uramoto H, Ono K, Takenoyama M, Hanagiri T, Oyama T, Izumi H, Kohno K, Yasumoto K (2010) Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status. J Thorac Oncol 5:591–596PubMed
go back to reference Pelosi G, Scarpa A, Manzotti M, Veronesi G, Spaggiari L, Fraggetta F, Nappi O, Benini E, Pasini F, Antonello D, Iannucci A, Maisonneuve P, Viale G (2004) K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung. Mod Pathol 17:538–546PubMedCrossRef Pelosi G, Scarpa A, Manzotti M, Veronesi G, Spaggiari L, Fraggetta F, Nappi O, Benini E, Pasini F, Antonello D, Iannucci A, Maisonneuve P, Viale G (2004) K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung. Mod Pathol 17:538–546PubMedCrossRef
go back to reference Pelosi G, Sonzogni A, De Pas T, Galetta D, Veronesi G, Spaggiari L, Manzotti M, Fumagalli C, Bresaola E, Nappi O, Viale G, Rosai J (2010) Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol 18:103–120PubMedCrossRef Pelosi G, Sonzogni A, De Pas T, Galetta D, Veronesi G, Spaggiari L, Manzotti M, Fumagalli C, Bresaola E, Nappi O, Viale G, Rosai J (2010) Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol 18:103–120PubMedCrossRef
go back to reference Rossi G, Cavazza A, Sturm N, Migaldi M, Facciolongo N, Longo L, Maiorana A, Brambilla E (2003) Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: a clinicopathologic and immunohistochemical study of 75 cases. Am J Surg Pathol 27:311–324PubMedCrossRef Rossi G, Cavazza A, Sturm N, Migaldi M, Facciolongo N, Longo L, Maiorana A, Brambilla E (2003) Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: a clinicopathologic and immunohistochemical study of 75 cases. Am J Surg Pathol 27:311–324PubMedCrossRef
go back to reference Ushiki A, Koizumi T, Kobayashi N, Kanda S, Yasuo M, Yamamoto H, Kubo K, Aoyagi D, Nakayama J (2009) Genetic heterogeneity of EGFR mutation in pleomorphic carcinoma of the lung: response to gefitinib and clinical outcome. Jpn J Clin Oncol 39:267–270PubMedCrossRef Ushiki A, Koizumi T, Kobayashi N, Kanda S, Yasuo M, Yamamoto H, Kubo K, Aoyagi D, Nakayama J (2009) Genetic heterogeneity of EGFR mutation in pleomorphic carcinoma of the lung: response to gefitinib and clinical outcome. Jpn J Clin Oncol 39:267–270PubMedCrossRef
Metadata
Title
Molecular profiles of EGFR, K-ras, c-met, and FGFR in pulmonary pleomorphic carcinoma, a rare lung malignancy
Authors
Soohyeon Lee
Youngwook Kim
Jong-Mu Sun
Yoon La Choi
Jhin Gook Kim
Young-Mog Shim
Yeon Hee Park
Jin Seok Ahn
Keunchil Park
Jung Ho Han
Myung-Ju Ahn
Publication date
01-08-2011
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 8/2011
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-011-0986-0

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