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BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Gene expression profiles of lung adenocarcinoma linked to histopathological grading and survival but not to EGF-R status: a microarray study

Authors: Jens Neumann, Friedrich Feuerhake, Gian Kayser, Thorsten Wiech, Konrad Aumann, Bernward Passlick, Paul Fisch, Martin Werner, Axel zur Hausen

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

Several different gene expression signatures have been proposed to predict response to therapy and clinical outcome in lung adenocarcinoma. Herein, we investigate if elements of published gene sets can be reproduced in a small dataset, and how gene expression profiles based on limited sample size relate to clinical parameters including histopathological grade and EGFR protein expression.

Methods

Affymetrix Human Genome U133A platform was used to obtain gene expression profiles of 28 pathologically and clinically annotated adenocarcinomas of the lung. EGFR status was determined by fluorescent in situ hybridization and immunohistochemistry.

Results

Using unsupervised clustering algorithms, the predominant gene expression signatures correlated with the histopathological grade but not with EGFR protein expression as detected by immunohistochemistry. In a supervised analysis, the signature of high grade tumors but not of EGFR overexpressing cases showed significant enrichment of gene sets reflecting MAPK activation and other potential signaling cascades downstream of EGFR. Out of four different previously published gene sets that had been linked to prognosis, three showed enrichment in the gene expression signature associated with favorable prognosis.

Conclusions

In this dataset, histopathological tumor grades but not EGFR status were associated with dominant gene expression signatures and gene set enrichment reflecting oncogenic pathway activation, suggesting that high immunohistochemistry EGFR scores may not necessarily be linked to downstream effects that cause major changes in gene expression patterns. Published gene sets showed association with patient survival; however, the small sample size of this study limited the options for a comprehensive validation of previously reported prognostic gene expression signatures.
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Literature
1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58 (2): 71-96. 10.3322/CA.2007.0010.CrossRefPubMed
2.
Travis W, Brambilla E, Müller-Hermelink K, Harris C: Tumours of the Lung, Pleura, Thymus and Heart. 2004, Lyon: IARC Press
3.
Sorensen JB, Hirsch FR, Gazdar A, Olsen JE: Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma. Cancer. 1993, 71 (10): 2971-2976. 10.1002/1097-0142(19930515)71:10<2971::AID-CNCR2820711014>3.0.CO;2-E.CrossRefPubMed
4.
Quackenbush J: Microarray analysis and tumor classification. N Engl J Med. 2006, 354 (23): 2463-2472. 10.1056/NEJMra042342.CrossRefPubMed
5.
Amatschek S, Koenig U, Auer H, Steinlein P, Pacher M, Gruenfelder A, Dekan G, Vogl S, Kubista E, Heider KH, et al: Tissue-wide expression profiling using cDNA subtraction and microarrays to identify tumor-specific genes. Cancer Res. 2004, 64 (3): 844-856. 10.1158/0008-5472.CAN-03-2361.CrossRefPubMed
6.
Balko JM, Potti A, Saunders C, Stromberg A, Haura EB, Black EP: Gene expression patterns that predict sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer cell lines and human lung tumors. BMC Genomics. 2006, 7: 289-10.1186/1471-2164-7-289.CrossRefPubMedPubMedCentral
7.
Bangur CS, Switzer A, Fan L, Marton MJ, Meyer MR, Wang T: Identification of genes over-expressed in small cell lung carcinoma using suppression subtractive hybridization and cDNA microarray expression analysis. Oncogene. 2002, 21 (23): 3814-3825. 10.1038/sj.onc.1205480.CrossRefPubMed
8.
Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, et al: Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002, 8 (8): 816-824.PubMed
9.
Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, et al: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA. 2001, 98 (24): 13790-13795. 10.1073/pnas.191502998.CrossRefPubMedPubMedCentral
10.
Borczuk AC, Gorenstein L, Walter KL, Assaad AA, Wang L, Powell CA: Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol. 2003, 163 (5): 1949-1960.CrossRefPubMedPubMedCentral
11.
Boutros PC, Lau SK, Pintilie M, Liu N, Shepherd FA, Der SD, Tsao MS, Penn LZ, Jurisica I: Prognostic gene signatures for non-small-cell lung cancer. Proc Natl Acad Sci USA. 2009, 106 (8): 2824-2828. 10.1073/pnas.0809444106.CrossRefPubMedPubMedCentral
12.
Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, Cheng CL, Wang CH, Terng HJ, Kao SF, et al: A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007, 356 (1): 11-20. 10.1056/NEJMoa060096.CrossRefPubMed
13.
Creighton C, Hanash S, Beer D: Gene expression patterns define pathways correlated with loss of differentiation in lung adenocarcinomas. FEBS Lett. 2003, 540 (1-3): 167-170. 10.1016/S0014-5793(03)00259-X.CrossRefPubMed
14.
Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, Rijn van de M, Rosen GD, Perou CM, Whyte RI, et al: Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA. 2001, 98 (24): 13784-13789. 10.1073/pnas.241500798.CrossRefPubMedPubMedCentral
15.
Gordon GJ, Jensen RV, Hsiao LL, Gullans SR, Blumenstock JE, Ramaswamy S, Richards WG, Sugarbaker DJ, Bueno R: Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. Cancer Res. 2002, 62 (17): 4963-4967.PubMed
16.
Gordon GJ, Richards WG, Sugarbaker DJ, Jaklitsch MT, Bueno R: A prognostic test for adenocarcinoma of the lung from gene expression profiling data. Cancer Epidemiol Biomarkers Prev. 2003, 12 (9): 905-910.PubMed
17.
Heighway J, Knapp T, Boyce L, Brennand S, Field JK, Betticher DC, Ratschiller D, Gugger M, Donovan M, Lasek A, et al: Expression profiling of primary non-small cell lung cancer for target identification. Oncogene. 2002, 21 (50): 7749-7763. 10.1038/sj.onc.1205979.CrossRefPubMed
18.
Hu J, Bianchi F, Ferguson M, Cesario A, Margaritora S, Granone P, Goldstraw P, Tetlow M, Ratcliffe C, Nicholson AG, et al: Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer. Oncogene. 2005, 24 (7): 1212-1219. 10.1038/sj.onc.1208242.CrossRefPubMed
19.
Kikuchi T, Daigo Y, Katagiri T, Tsunoda T, Okada K, Kakiuchi S, Zembutsu H, Furukawa Y, Kawamura M, Kobayashi K, et al: Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene. 2003, 22 (14): 2192-2205. 10.1038/sj.onc.1206288.CrossRefPubMed
20.
Kobayashi K, Nishioka M, Kohno T, Nakamoto M, Maeshima A, Aoyagi K, Sasaki H, Takenoshita S, Sugimura H, Yokota J: Identification of genes whose expression is upregulated in lung adenocarcinoma cells in comparison with type II alveolar cells and bronchiolar epithelial cells in vivo. Oncogene. 2004, 23 (17): 3089-3096. 10.1038/sj.onc.1207433.CrossRefPubMed
21.
Larsen JE, Pavey SJ, Passmore LH, Bowman RV, Hayward NK, Fong KM: Gene expression signature predicts recurrence in lung adenocarcinoma. Clin Cancer Res. 2007, 13 (10): 2946-2954. 10.1158/1078-0432.CCR-06-2525.CrossRefPubMed
22.
Miura K, Bowman ED, Simon R, Peng AC, Robles AI, Jones RT, Katagiri T, He P, Mizukami H, Charboneau L, et al: Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Res. 2002, 62 (11): 3244-3250.PubMed
23.
Moran CJ, Arenberg DA, Huang CC, Giordano TJ, Thomas DG, Misek DE, Chen G, Iannettoni MD, Orringer MB, Hanash S, et al: RANTES expression is a predictor of survival in stage I lung adenocarcinoma. Clin Cancer Res. 2002, 8 (12): 3803-3812.PubMed
24.
Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Saijo T, Kawasaki N, Kato H: cDNA microarray analysis of gene expression in pathologic Stage IA nonsmall cell lung carcinomas. Cancer. 2003, 97 (11): 2798-2805. 10.1002/cncr.11406.CrossRefPubMed
25.
Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A, Koontz J, Kratzke R, Watson MA, Kelley M, Ginsburg GS, et al: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med. 2006, 355 (6): 570-580. 10.1056/NEJMoa060467.CrossRefPubMed
26.
Raponi M, Zhang Y, Yu J, Chen G, Lee G, Taylor JM, Macdonald J, Thomas D, Moskaluk C, Wang Y, et al: Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. Cancer Res. 2006, 66 (15): 7466-7472. 10.1158/0008-5472.CAN-06-1191.CrossRefPubMed
27.
Stearman RS, Dwyer-Nield L, Grady MC, Malkinson AM, Geraci MW: A macrophage gene expression signature defines a field effect in the lung tumor microenvironment. Cancer Res. 2008, 68 (1): 34-43. 10.1158/0008-5472.CAN-07-0988.CrossRefPubMed
28.
Tonon G, Wong KK, Maulik G, Brennan C, Feng B, Zhang Y, Khatry DB, Protopopov A, You MJ, Aguirre AJ, et al: High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci USA. 2005, 102 (27): 9625-9630. 10.1073/pnas.0504126102.CrossRefPubMedPubMedCentral
29.
Wigle DA, Jurisica I, Radulovich N, Pintilie M, Rossant J, Liu N, Lu C, Woodgett J, Seiden I, Johnston M, et al: Molecular profiling of non-small cell lung cancer and correlation with disease-free survival. Cancer Res. 2002, 62 (11): 3005-3008.PubMed
30.
Granville CA, Dennis PA: An overview of lung cancer genomics and proteomics. Am J Respir Cell Mol Biol. 2005, 32 (3): 169-176. 10.1165/rcmb.F290.CrossRefPubMed
31.
Onn A, Tsuboi M, Thatcher N: Treatment of non-small-cell lung cancer: a perspective on the recent advances and the experience with gefitinib. Br J Cancer. 2004, 91 (Suppl 2): S11-17. 10.1038/sj.bjc.6602062.CrossRefPubMedPubMedCentral
32.
Shedden K, Taylor JM, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL, Eschrich S, Jurisica I, Giordano TJ, Misek DE, et al: Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med. 2008, 14 (8): 822-827. 10.1038/nm.1790.CrossRefPubMedPubMedCentral
33.
Liu G, Loraine AE, Shigeta R, Cline M, Cheng J, Valmeekam V, Sun S, Kulp D, Siani-Rose MA: NetAffx: Affymetrix probesets and annotations. Nucleic Acids Res. 2003, 31 (1): 82-86. 10.1093/nar/gkg121.CrossRefPubMedPubMedCentral
34.
Barrett T, Suzek TO, Troup DB, Wilhite SE, Ngau WC, Ledoux P, Rudnev D, Lash AE, Fujibuchi W, Edgar R: NCBI GEO: mining millions of expression profiles--database and tools. Nucleic Acids Res. 2005, D562-566. 33 Database
35.
Cappola TP, Cope L, Cernetich A, Barouch LA, Minhas K, Irizarry RA, Parmigiani G, Durrani S, Lavoie T, Hoffman EP, et al: Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy. Physiol Genomics. 2003, 14 (1): 25-34.CrossRefPubMed
36.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003, 4 (2): 249-264. 10.1093/biostatistics/4.2.249.CrossRefPubMed
37.
Gautier L, Cope L, Bolstad BM, Irizarry RA: affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004, 20 (3): 307-315. 10.1093/bioinformatics/btg405.CrossRefPubMed
38.
Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP: GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics. 2007, 23 (23): 3251-3253. 10.1093/bioinformatics/btm369.CrossRefPubMed
39.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005, 102 (43): 15545-15550. 10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral
40.
Petersen I, Kotb WF, Friedrich KH, Schluns K, Bocking A, Dietel M: Core classification of lung cancer: Correlating nuclear size and mitoses with ploidy and clinicopathological parameters. Lung Cancer. 2009, 65 (3): 312-318. 10.1016/j.lungcan.2008.12.013.CrossRefPubMed
41.
Dacic S, Flanagan M, Cieply K, Ramalingam S, Luketich J, Belani C, Yousem SA: Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol. 2006, 125 (6): 860-865. 10.1309/H5UW6CPCWWC92241.CrossRefPubMed
42.
Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA: Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer. 2003, 41 (Suppl 1): S29-42. 10.1016/S0169-5002(03)00137-5.CrossRefPubMed
43.
Hirsch FR, Varella-Garcia M, Bunn PA, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA: Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003, 21 (20): 3798-3807. 10.1200/JCO.2003.11.069.CrossRefPubMed
44.
Motoi N, Szoke J, Riely GJ, Seshan VE, Kris MG, Rusch VW, Gerald WL, Travis WD: Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008, 32 (6): 810-827. 10.1097/PAS.0b013e31815cb162.CrossRefPubMed
Metadata
Title
Gene expression profiles of lung adenocarcinoma linked to histopathological grading and survival but not to EGF-R status: a microarray study
Authors
Jens Neumann
Friedrich Feuerhake
Gian Kayser
Thorsten Wiech
Konrad Aumann
Bernward Passlick
Paul Fisch
Martin Werner
Axel zur Hausen
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-77

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