Adenocarcinoma

Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 6)

Abstract

Adenocarcinoma of the lung is an extremely complex, heterogeneous group of tumours which display an extraordinary range of clinical and biological behaviour. This diversity is reflected in the morphology of the tumour and also in the emerging data on their molecular biology. Adenocarcinomas of the lung demonstrate, in common with malignancies of other histotype, molecular features which account for the so-called hallmarks of cancer, alterations in numerous genes function which leads to consistent aberrant cell population behaviour, all of which combine, resulting in the malignant phenotype. Much of the literature on adenocarcinoma molecular biology has moved away from a focus on particular genes or pathways to employ more global genomic assays of various types. From this has emerged an almost overwhelming amount of data, huge challenges in bioinformatics and interpretation but equally huge opportunities to understand complex inter-relationships between different molecular pathways. One of the most exciting aspects of the new data on lung adenocarcinoma molecular biology is the apparent tendency for a proportion of these tumours to demonstrate the so-called oncogene addiction. The importance of a particular genetic lesion, usually, though not exclusively, an activating mutation, being the sole or dominant driver of the malignant phenotype is that pharmacological inhibition of the resultant oncogenic mutant protein can lead to spectacular clinical response to treatment. The most important genes so far identified, whose abnormal expression appears to play a dominant role in individual cases, and which offer potential therapeutic targets, include EGFR, KRAS, ALK, BRAF, HER2 and CMET. Interesting uses of molecular markers in the diagnosis and classification of lung adenocarcinoma, and correlations between tumour morphology and molecular changes complete an extensive and constantly increasing body of literature on the molecular biology of lung adenocarcinoma.

Keywords

Codon Polycyclic Aromatic Hydrocarbon Serine Sarcoma Folate 

References

  1. 1.
    Colby TV, Noguchi M, Henschke C, et al. Adenocarcinoma. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., editors. Pathology and genetics of tumours of the lung, pleura, thymus and heart, World Health Organisation Classification of Tumours. Lyon: IARC; 2004. p. 35–44.Google Scholar
  2. 2.
    Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol. 2011;6:244–85.PubMedGoogle Scholar
  3. 3.
    Kerr KM. Pulmonary adenocarcinomas: classification and reporting. Histopathology. 2009;54:12–27.PubMedGoogle Scholar
  4. 4.
    Kerr KM, Fyfe MN, Nicolson MC, et al. Influence of tumour patterns in mixed-type adenocarcinoma on post-operative survival. J Thorac Oncol. 2007;2(supp 4):S801–2.Google Scholar
  5. 5.
    Motoi N, Szoke J, Riely GJ, et al. 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: 810–27.PubMedGoogle Scholar
  6. 6.
    Yatabe Y, Mitsudomi T, Takahashi T. TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol. 2002;26:767–73.PubMedGoogle Scholar
  7. 7.
    Kerr KM, Fraire AE. Pre-invasive Diseases. In: Tomashefski J, Cagle P, Farver C, editors. Dail & Hammar’s pulmonary pathology. 3rd ed. New York: Springer; 2008.Google Scholar
  8. 8.
    Kerr KM, Fraire AE, Pugatch B, et al. Atypical adenomatous hyperplasia. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., editors. Pathology and genetics of tumours of the lung, pleura, thymus and heart, World Health Organisation Classification of Tumours. Lyon: IARC; 2004. p. 73–5.Google Scholar
  9. 9.
    Kaye FJ. Molecular biology of lung cancer. Lung Cancer. 2001;34:S35–41.PubMedGoogle Scholar
  10. 10.
    Mao L. Molecular abnormalities in lung carcinogenesis and their potential clinical implications. Lung Cancer. 2001;34:S27–34.PubMedGoogle Scholar
  11. 11.
    Sato M, Shames DS, Gazdar AF, et al. A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol. 2007;2:327–43.PubMedGoogle Scholar
  12. 12.
    Schatzkin A. Sir Richard Doll on chance and genetic susceptibility in carcinogenesis, or, why not all smokers get lung cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1420.PubMedGoogle Scholar
  13. 13.
    Doll R. Commentary: the age distribution of cancer and a multistage theory of carcinogenesis. Int J Epidemiol. 2004;33:1183–4.PubMedGoogle Scholar
  14. 14.
    Weinstein IB. Cancer. Addiction to oncogenes—the Achilles heel of cancer. Science. 2002;297:63–4.PubMedGoogle Scholar
  15. 15.
    Pao W, Iafrate AJ, Su Z. Genetically informed lung cancer medicine. J Pathol. 2011;223:230–40.PubMedGoogle Scholar
  16. 16.
    Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175–80.PubMedGoogle Scholar
  17. 17.
    Kerr KM. Personalized medicine in lung cancer: new challenges for pathologists. Histopathology. 2011;60(4):531–46.PubMedGoogle Scholar
  18. 18.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedGoogle Scholar
  19. 19.
    Sekido Y, Fong KM, Minna JD. Molecular genetics of lung cancer. Annu Rev Med. 2003;54:73–87.PubMedGoogle Scholar
  20. 20.
    Fong KM, Sekido Y, Gazdar AF, et al. Molecular biology of lung cancer: clinical implications. Thorax. 2003;58:892–900.PubMedGoogle Scholar
  21. 21.
    Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323: 561–5.PubMedGoogle Scholar
  22. 22.
    Shay JW, Wright WE. Telomerase therapeutics for cancer: challenges and new directions. Nat Rev Drug Discov. 2006;5:577–84.PubMedGoogle Scholar
  23. 23.
    Fernandez-Garcia I, Ortiz-de-Solorzano C, Montuenga LM. Telomeres and telomerase in lung cancer. J Thorac Oncol. 2008;3:1085–8.PubMedGoogle Scholar
  24. 24.
    Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trail comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2004;22:2184–91.PubMedGoogle Scholar
  25. 25.
    Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med. 2006;355:2542–50.PubMedGoogle Scholar
  26. 26.
    Coghlin C, Murray GI. Current and emerging concepts in tumour metastases. J Pathol. 2010;222:1–15.PubMedGoogle Scholar
  27. 27.
    Kerr KM, MacKenzie SJ, Ramasami S, et al. Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma. J Pathol. 2004;203:638–44.PubMedGoogle Scholar
  28. 28.
    Choi JS, Zheng LT, Ha E, et al. Comparative genomic hybridization array analysis and real-time PCR reveals genomic copy number alteration for lung adenocarcinomas. Lung. 2006;184:355–62.PubMedGoogle Scholar
  29. 29.
    Aviel-Ronen S, Coe BP, Lau SK, et al. Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioalveolar features. Proc Natl Acad Sci U S A. 2008;22:10155–60.Google Scholar
  30. 30.
    Shen H, Zhu Y, Wu YJ, et al. Genomic alterations in lung adenocarcinomas detected by multicolour fluorescence in situ hybridization and comparative genomic hybridization. Cancer Genet Cytogenet. 2008;181:100–7.PubMedGoogle Scholar
  31. 31.
    Shen H, Gao W, Wu YJ, et al. Multicolor fluorescence in situ hybridization and comparative genomic hybridization reveal molecular events in lung adenocarcinomas and squamous cell lung carcinomas. Biomed Pharmacother. 2009;63:396–403.PubMedGoogle Scholar
  32. 32.
    Sung JS, Park KH, Kim YH. Genomic alterations of chromosome region 11p as predictive marker by array comparative genomic hybridization in lung adenocarcinoma patients. Cancer Genet Cytogenet. 2010;198:27–34.PubMedGoogle Scholar
  33. 33.
    Sy SM, Wong N, Mok TS, et al. Genetic alterations of lung adenocarcinoma in relation to smoking and ethnicity. Lung Cancer. 2003;41:91–9.PubMedGoogle Scholar
  34. 34.
    Wong MP, Fung LF, Wang E, et al. Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers. Cancer. 2003;97:1263–70.PubMedGoogle Scholar
  35. 35.
    Job B, Bernheim A, Beau-Faller M, et al. Genomic aberrations in lung adenocarcinoma in never smokers. PLoS One. 2010;5(12):e15145.PubMedGoogle Scholar
  36. 36.
    Shibata T, Uryu S, Kokubu A, et al. Genetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: its association with clinicopathologic features. Clin Cancer Res. 2005;11:6177–85.PubMedGoogle Scholar
  37. 37.
    Weir BA, Woo MS, Getz G, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007;450:893–901.PubMedGoogle Scholar
  38. 38.
    Petty RD, Nicolson MC, Kerr KM, et al. Gene expression profiling in non-small cell lung cancer: from molecular mechanisms to clinical application. Clin Cancer Res. 2004;10:3237–48.PubMedGoogle Scholar
  39. 39.
    Zhu CQ, Pintilie M, John T, et al. Understanding prognostic gene expression signatures in lung cancer. Clin Lung Cancer. 2009;10:331–40.PubMedGoogle Scholar
  40. 40.
    Dacic S. Molecular diagnostics in lung cancer. In: Cagle PT, Allen TC, Dacic S, Kerr KM, Beasley MB, editors. Advances in surgical pathology: lung cancer. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 189–97.Google Scholar
  41. 41.
    Garber ME, Troyanskaya OG, Schluens K, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 2001;98:13784–9.PubMedGoogle Scholar
  42. 42.
    Bhattacharjee A, Richards WG, Staunton J, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A. 2001;98: 13790–5.PubMedGoogle Scholar
  43. 43.
    Beer DG, Kardia SLR, Huang C, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002;8:816–24.PubMedGoogle Scholar
  44. 44.
    Takeuchi T, Tomida S, Yatabe Y, et al. Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathological behaviors. J Clin Oncol. 2006;24:1679–88.PubMedGoogle Scholar
  45. 45.
    Hayes DN, Monti S, Parmigiani G, et al. Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts. J Clin Oncol. 2006;24:5079–90.PubMedGoogle Scholar
  46. 46.
    Borczuk AC, Kim HK, Yegen HA, et al. Lung adenocarcinoma global profiling identifies type II transforming growth factor-beta receptor as a repressor of invasiveness. Am J Respir Crit Care Med. 2005;172: 729–37.PubMedGoogle Scholar
  47. 47.
    Toonkel RL, Borczuk AC, Powell CA. Tgf-beta signalling pathway in lung adenocarcinoma invasion. J Thorac Oncol. 2010;5:153–7.PubMedGoogle Scholar
  48. 48.
    Noguchi M, Morokawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995;75:2844–52.PubMedGoogle Scholar
  49. 49.
    Tomida S, Koshikawa K, Yatabe Y, et al. Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients. Oncogene. 2004;23:5360–70.PubMedGoogle Scholar
  50. 50.
    Chen HY, Yu SL, Chen CH, et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007;356:11–20.PubMedGoogle Scholar
  51. 51.
    Lu Y, Lemon W, Liu PY, et al. A gene expression signature predicts survival of patients with stage I non-small cell lung carcinoma. PLoS Med. 2006;3:e467.PubMedGoogle Scholar
  52. 52.
    Potti A, Mukherjee S, Petersen R, et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med. 2006;355:570–80.PubMedGoogle Scholar
  53. 53.
    Gordon GJ, Richards WG, Sugarbaker DJ, et al. A prognostic test for adenocarcinoma of the lung from gene expression profiling data. Cancer Epidemiol Biomarkers Prev. 2003;12:905–10.PubMedGoogle Scholar
  54. 54.
    Larsen JE, Pavey SJ, Passmore LH, et al. Gene expression signature predicts recurrence in lung adenocarcinoma. Clin Cancer Res. 2007;13:2946–54.PubMedGoogle Scholar
  55. 55.
    Takada M, Tada M, Tamoto E, et al. Prediction of lymph node metastasis by analysis of gene expression profiles in non-small cell lung cancer. J Surg Res. 2004;122:61–9.PubMedGoogle Scholar
  56. 56.
    Xi L, Lyons-Weiler J, Coello MC, et al. Prediction of lymph node metastasis by analysis of gene expression profiles in primary lung adenocarcinomas. Clin Cancer Res. 2005;11:4128–35.PubMedGoogle Scholar
  57. 57.
    Choi N, Son D-S, Lee K, et al. The signature from messenger RNA expression profiling can predict lymph node metastasis with high accuracy for non-small cell lung cancer. J Thorac Oncol. 2006;1:622–8.PubMedGoogle Scholar
  58. 58.
    Boutros PC, Lau SK, Pintilie M, et al. Prognostic gene signatures for non-small-cell lung cancer. PNAS. 2009;106:2824–8.PubMedGoogle Scholar
  59. 59.
    Endoh H, Tomida S, Yatabe Y, et al. Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. J Clin Oncol. 2004;22:811–9.PubMedGoogle Scholar
  60. 60.
    Guo L, Ma Y, Ward R, et al. Constructing molecular classifiers for the accurate prognosis of lung adenocarcinoma. Clin Cancer Res. 2006;12:3344–54.PubMedGoogle Scholar
  61. 61.
    Sun Z, Yang P, Aubry MC, et al. Can gene expression profiling predict survival for patients with squamous cell carcinoma of the lung? Mol Cancer. 2004;3:35.PubMedGoogle Scholar
  62. 62.
    Raponi M, Zhang Y, Yu J, et al. Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. Cancer Res. 2006;66:7466–72.PubMedGoogle Scholar
  63. 63.
    Reed CE, Graham A, Hoda RS, et al. A simple two-gene prognostic model for adenocarcinoma of the lung. J Thorac Cardiovasc Surg. 2008;135:627–34.PubMedGoogle Scholar
  64. 64.
    Shedden K, Taylor JMG, Enkemann S, et al. Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med. 2008;14:822–7.PubMedGoogle Scholar
  65. 65.
    Coate LE, John T, Tsao MS, et al. Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet. 2009;10:1001–10.Google Scholar
  66. 66.
    Dobbin KK, Beer DG, Meyerson M, et al. Interlaboratory comparability study of cancer gene expression analysis using oligonucleotide microarrays. Clin Cancer Res. 2005;11:565–72.PubMedGoogle Scholar
  67. 67.
    Bryant CM, Albertus DL, Kim S, et al. Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study. PLoS One. 2010;5:e11712.PubMedGoogle Scholar
  68. 68.
    Borczuk AC, Shah L, Pearson GD, et al. Molecular signatures in biopsy specimens of lung cancer. Am J Respir Crit Care Med. 2004;170:167–74.PubMedGoogle Scholar
  69. 69.
    Lee W, Jiang Z, Liu J, et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 2010;465:473–7.PubMedGoogle Scholar
  70. 70.
    Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–75.PubMedGoogle Scholar
  71. 71.
    Bae NC, Chae MH, Lee MH, et al. EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients. Cancer Genet Cytogenet. 2007;173:107–13.PubMedGoogle Scholar
  72. 72.
    Sun Y, Ren Y, Fang Z, et al. Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol. 2010;28:4616–20.PubMedGoogle Scholar
  73. 73.
    Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res. 2006;12:1647–53.PubMedGoogle Scholar
  74. 74.
    Suzuki M, Shigematsu H, Iizasa T, et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer. 2006;106:2200–7.PubMedGoogle Scholar
  75. 75.
    Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature. 2007;448:561–6.PubMedGoogle Scholar
  76. 76.
    Rosell R, Cuello M, Cecere F, et al. Treatment of non-small-cell lung cancer and pharmacogenomics: where we are and where we are going. Curr Opin Oncol. 2006;18:135–43.PubMedGoogle Scholar
  77. 77.
    Assaraf YG. Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007;26:153–81.PubMedGoogle Scholar
  78. 78.
    Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared to other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107:1589–96.PubMedGoogle Scholar
  79. 79.
    Monica V, Scagliotti GV, Ceppi P, et al. Differential thymidylate synthase expression in different variants of large cell carcinoma of the lung. Clin Cancer Res. 2009;15:7547–52.PubMedGoogle Scholar
  80. 80.
    Scagliotti GV, Parikh P, Pawel JV, et al. Phase III study comparing Cisplatin plus Gemcitabine with Cisplatin plus Pemetrexed in chemotherapy-naive patients with advanced-stage non-small cell lung cancer. J Clin Oncol. 2008;26:1–10.Google Scholar
  81. 81.
    Hanna N, Shepherd FA, Fossella FV, et al. Randomised phase III trail of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–97.PubMedGoogle Scholar
  82. 82.
    Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009;14:253–63.PubMedGoogle Scholar
  83. 83.
    Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432–40.PubMedGoogle Scholar
  84. 84.
    Gazdar AF. Personalised medicine and inhibition of EGFR signalling in lung cancer. New Engl J Med. 2009;361:1018–20.PubMedGoogle Scholar
  85. 85.
    Gazdar AF, Minna JD. Deregulated EGFR signaling during lung cancer progression: mutations, amplicons, and autocrine loops. Cancer Prev Res (Phila). 2008;1:156–60.Google Scholar
  86. 86.
    Awaya H, Takeshima Y, Furonaka O, et al. Gene amplification and protein expression of EGFR and HER2 by chromogenic in situ hybridisation and immunohistochemistry in atypical adenomatous hyperplasia and adenocarcinoma of the lung. J Clin Pathol. 2005;58:1076–80.PubMedGoogle Scholar
  87. 87.
    Kim ES, Hirsh V, Mok T, et al. Gefitinib versus ­docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809–18.PubMedGoogle Scholar
  88. 88.
    Clark GM, Zborowski DM, Culbertson JL, et al. Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol. 2006;1:837–46.PubMedGoogle Scholar
  89. 89.
    Hirsch FR, Dziadziuszko R, Thatcher N, et al. Epidermal growth factor receptor immunohistochemistry. Cancer. 2008;112:1114–21.PubMedGoogle Scholar
  90. 90.
    Zhu CQ, Shih W, Ling CH, et al. Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. J Clin Pathol. 2006;59:790–800.PubMedGoogle Scholar
  91. 91.
    Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525–31.PubMedGoogle Scholar
  92. 92.
    Hirsch FR, Varella-Garcia M, Bunn Jr PA, et al. 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;21:3798–807.PubMedGoogle Scholar
  93. 93.
    Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55.PubMedGoogle Scholar
  94. 94.
    Gupta R, Dastane AM, Forozan F, et al. Evaluation of EGFR abnormalities in patients with pulmonary adenocarcinoma: the need to test neoplasms with more than one method. Mod Pathol. 2009;22:128–33.PubMedGoogle Scholar
  95. 95.
    Gupta R, Dastane AM, McKenna R, et al. The predictive value of epidermal growth factor receptor tests in patients with pulmonary adenocarcinoma: review of current “best evidence” with meta-analysis. Hum Pathol. 2009;40:356–65.PubMedGoogle Scholar
  96. 96.
    Soh J, Okumura N, Lockwood WW, et al. Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumour cells. PLoS One. 2009;4:e7464.PubMedGoogle Scholar
  97. 97.
    Italiano A, Vandenbos FB, Otto J, et al. Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors. Ann Oncol. 2006;17:981–5.PubMedGoogle Scholar
  98. 98.
    Bozzetti C, Tiseo M, Lagrasta C, et al. Comparison between epidermal growth factor receptor (EGFR) gene expression in primary non-small cell lung cancer (NSCLC) and in fine-needle aspirates from distant metastatic sites. J Thorac Oncol. 2008;3:18–22.PubMedGoogle Scholar
  99. 99.
    Prudkin L, Wistuba II. Epidermal growth factor receptor abnormalities in lung cancer. Pathogenic and clinical implications. Ann Diagn Pathol. 2006; 10:306–15.PubMedGoogle Scholar
  100. 100.
    Riely GJ, Politi KA, Miller VA, et al. Update on epidermal growth factor receptor mutations in non-small lung cancer. Clin Cancer Res. 2006;12:7232–41.PubMedGoogle Scholar
  101. 101.
    Mitsudomi T, Kosaki T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol. 2006;11:190–8.PubMedGoogle Scholar
  102. 102.
    Sasaki H, Shimizu S, Endo K, et al. EGFR and erbB2 mutation status in Japanese lung cancer patients. Int J Cancer. 2006;1:180–4.Google Scholar
  103. 103.
    Lee SY, Kim MJ, Jin G, et al. Somatic mutations in epidermal growth factor receptor signalling pathway genes in non-small cell lung cancers. J Thorac Oncol. 2010;5:1734–40.PubMedGoogle Scholar
  104. 104.
    Reinmuth N, Jauch A, Xu EC, et al. Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients. Lung Cancer. 2008;62:193–201.PubMedGoogle Scholar
  105. 105.
    Pham DK, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol. 2006;24:1700–4.PubMedGoogle Scholar
  106. 106.
    Lee YJ, Shim HS, Kang YA, et al. Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer. J Cancer Res Clin Oncol. 2010;136(12):1937–44. doi: 10.1007/s00432-010-0853-4.PubMedGoogle Scholar
  107. 107.
    Sartori G, Cavazza A, Sgambato A, et al. EGFR and K-ras mutations along the spectrum of pulmonary epithelial tumors of the lung and elaboration of a combined clinicopathologic and molecular scoring system to predict clinical responsiveness to EGFR inhibitors. Am J Clin Pathol. 2009;131:478–89.PubMedGoogle Scholar
  108. 108.
    Marchetti A, Martella C, Felicioni L, et al. 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. 2005;23:857–65.PubMedGoogle Scholar
  109. 109.
    Tsao AS, Tang XM, Sabloff B, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol. 2006;1: 231–9.PubMedGoogle Scholar
  110. 110.
    Lee KH, Min HS, Han SW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer. Lung Cancer. 2008;60:401–7.PubMedGoogle Scholar
  111. 111.
    Li AR, Chitale D, Riely GJ, et al. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn. 2008;10:242–8.PubMedGoogle Scholar
  112. 112.
    Paez JG, Janne PA, Lee JC, et al. EGRF mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.PubMedGoogle Scholar
  113. 113.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med. 2004;350: 2129–39.PubMedGoogle Scholar
  114. 114.
    Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol. 2005;23:2556–68.PubMedGoogle Scholar
  115. 115.
    Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.PubMedGoogle Scholar
  116. 116.
    Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small cell lung cancer with mutated EGFR. New Engl J Med. 2010;362:2380–8.PubMedGoogle Scholar
  117. 117.
    Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus dicetaxel in patients with non small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 2010;11:121–8.PubMedGoogle Scholar
  118. 118.
    Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. New Engl J Med. 2009;361:958–67.PubMedGoogle Scholar
  119. 119.
    Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29:37–48.PubMedGoogle Scholar
  120. 120.
    Murray S, Dahabreh IJ, Linardou H, et al. Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J Thorac Oncol. 2008;3:832–9.PubMedGoogle Scholar
  121. 121.
    Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169–81.PubMedGoogle Scholar
  122. 122.
    Yatabe Y. EGFR mutations and the terminal respiratory unit. Cancer Metastasis Rev. 2010;29:23–36.PubMedGoogle Scholar
  123. 123.
    Faber AC, Wong KK, Engelman JA. Differences underlying EGFR and HER2 oncogene addiction. Cell Cycle. 2010;9:851–2.PubMedGoogle Scholar
  124. 124.
    Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009;69:3256–61.PubMedGoogle Scholar
  125. 125.
    Rosell R, Molina MA, Costa C, et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlitinib-treated advanced non-small cell lung cancer patients with EGFR mutations. Clin Cancer Res. 2011;17(5):1160–8. doi: 10.1158/1078-0432.CCR-10-2158.PubMedGoogle Scholar
  126. 126.
    Turke AB, Zejnullahu K, Wu Y-L, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77–88.PubMedGoogle Scholar
  127. 127.
    Noguchi M. Stepwise progression of pulmonary adenocarcinoma—clinical and molecular implications. Cancer Metastasis Rev. 2010;29:15–21.PubMedGoogle Scholar
  128. 128.
    Yatabe Y, Kosaka T, Takahashi T, et al. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol. 2005;29:633–9.PubMedGoogle Scholar
  129. 129.
    Yoshida Y, Sibata T, Kokubu A, et al. Mutations of the epidermal growth factor receptor gene in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma of the lung. Lung Cancer. 2005;49 Suppl 2:S76.Google Scholar
  130. 130.
    Kozuki T, Hisamoto A, Tabata M, et al. Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung. Lung Cancer. 2007;58:30–5.PubMedGoogle Scholar
  131. 131.
    Sakuma Y, Matsukuma S, Yoshihara M, et al. Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung. Mod Pathol. 2007;20:967–73.PubMedGoogle Scholar
  132. 132.
    Sakamoto H, Shimizu J, Horio Y, et al. Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol. 2007;212:287–94.PubMedGoogle Scholar
  133. 133.
    Ikeda K, Nomori H, Ohba Y, et al. Epidermal growth factor receptor mutations in multicentric lung adenocarcinomas and atypical adenomatous hyperplasias. J Thorac Oncol. 2008;3:467–71.PubMedGoogle Scholar
  134. 134.
    Sartori G, Cavazza A, Bertolini F, et al. A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis. Am J Clin Pathol. 2008;129:202–10.PubMedGoogle Scholar
  135. 135.
    Yoo SB, Chung JH, Lee HJ, et al. Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung. J Thorac Oncol. 2010;5:964–9.PubMedGoogle Scholar
  136. 136.
    Tang X, Shigematsu H, Bekele BN, et al. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res. 2005;65:7568–72.PubMedGoogle Scholar
  137. 137.
    Kwei KA, Kim YH, Girard L, et al. Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene. 2008;27: 3635–40.PubMedGoogle Scholar
  138. 138.
    Nakanishi H, Matsumoto S, Iwakawa R, et al. Whole genome comparison of allelic imbalance between non-invasive and invasive small sized lung adenocarcinoma. Can Res. 2009;69:1615–23.Google Scholar
  139. 139.
    Schmid K, Oehl N, Wrba F, et al. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res. 2009;15:4554–60.PubMedGoogle Scholar
  140. 140.
    Park S, Holmes-Tisch AJ, Cho EY, et al. Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumours and lymph node metastasis in non-small cell lung cancer. J Thorac Oncol. 2009;4:809–15.PubMedGoogle Scholar
  141. 141.
    Hirsch FR, Varella-Garcia M, Cappuzzo F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene. 2009;28:32–7.Google Scholar
  142. 142.
    Hirsch FR, Varella-Garcia M, Franklin WA, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer. 2002;86:1449–56.PubMedGoogle Scholar
  143. 143.
    Toh CK, Ahmad B, Soong R, et al. Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas. J Thorac Oncol. 2010;5:17–22.PubMedGoogle Scholar
  144. 144.
    Al-Saad S, Al-Shibli K, Donnem T, et al. Clinical significance of epidermal growth factor receptors in non-small cell lung cancer and a prognostic role for HER2 gene copy number in female patients. J Thorac Oncol. 2010;5:1536–43.PubMedGoogle Scholar
  145. 145.
    Kerr KM, Carey FA, King G, et al. Atypical alveolar hyperplasia: relationship with pulmonary adenocarcinoma, p53 and c-erbB-2 expression. J Pathol. 1994;174:249–56.PubMedGoogle Scholar
  146. 146.
    Liu L, Shae X, Gao W, et al. The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer: a meta-analysis of published data. J Thorac Oncol. 2010;5:1922–32.PubMedGoogle Scholar
  147. 147.
    Soh J, Toyooka S, Ichihara S, et al. Impact of HER2 and EGFR gene status on gefitinib-treated patients with nonsmall-cell lung cancer. Int J Cancer. 2007;121:1162–7.PubMedGoogle Scholar
  148. 148.
    Gandhi J, Zhang J, Xie Y, et al. Alterations in genes of the EGFR signalling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One. 2009;4(2):e4576.PubMedGoogle Scholar
  149. 149.
    Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 2007;98:1817–24.PubMedGoogle Scholar
  150. 150.
    Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65:1642–6.PubMedGoogle Scholar
  151. 151.
    Buttitta F, Barassi F, Fresu G, et al. Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int J Cancer. 2006;119:2586–91.PubMedGoogle Scholar
  152. 152.
    Yokoyama T, Kondo M, Goto Y, et al. EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci. 2006;97:753–9.PubMedGoogle Scholar
  153. 153.
    Mounawar M, Mukeria A, Le Calvez F, et al. Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. Cancer Res. 2007;67:5667–72.PubMedGoogle Scholar
  154. 154.
    Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med. 2006;354:2619–21.PubMedGoogle Scholar
  155. 155.
    Doebele RC, Oton AB, Peled N, et al. New strategies to overcome limitations of reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer. Lung Cancer. 2010;69:1–12.PubMedGoogle Scholar
  156. 156.
    Spicer JF, Rudman SM. EGFR inhibitors in non-small lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol. 2010;5:245–55.PubMedGoogle Scholar
  157. 157.
    Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Met Rev. 2010;29:49–60.Google Scholar
  158. 158.
    Roberts PJ, Stinchcombe TE, Der CJ, et al. Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol. 2010;28:4769–77.PubMedGoogle Scholar
  159. 159.
    Kobayashi T, Tsuda H, Noguchi M, et al. Association of point mutation in c-Ki-ras oncogene in lung adenocarcinoma with particular reference to cytologic subtypes. Cancer. 1990;66:289–94.PubMedGoogle Scholar
  160. 160.
    Marks JL, McLellan MD, Zakowski MF, et al. Mutational analysis of EGFR and related signalling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. PLoS One. 2007;2(5):e426.PubMedGoogle Scholar
  161. 161.
    Shibata T, Hanada S, Kobubu A, et al. Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma. Cancer Sci. 2007;98:985–91.PubMedGoogle Scholar
  162. 162.
    Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201–5.PubMedGoogle Scholar
  163. 163.
    Kosaka T, Yatabe Y, Endoh M, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 2004;64:8919–23.PubMedGoogle Scholar
  164. 164.
    Dacic S, Shuai Y, Yousem S, et al. Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas. Mod Pathol. 2010;23:159–68.PubMedGoogle Scholar
  165. 165.
    Kim YT, Kim TY, Lee DS, et al. Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung. Lung Cancer. 2008;59:111–8.PubMedGoogle Scholar
  166. 166.
    Marchetti A, Milella M, Felicioni L, et al. Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones. Neoplasia. 2009;11:1084–92.PubMedGoogle Scholar
  167. 167.
    Mascaux C, Iannino N, Martin B, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2005;92:131–9.PubMedGoogle Scholar
  168. 168.
    Sagawa M, Saito Y, Fujimura S, et al. K-ras point mutation occurs in the early stage of carcinogenesis in lung cancer. Br J Cancer. 1998;77:720–3.PubMedGoogle Scholar
  169. 169.
    Ohshima S, Shimizu Y, Takahama M. Detection of c-Ki-ras gene mutation in paraffin sections of adenocarcinoma and atypical bronchioloalveolar cell hyperplasia of human lung. Virchows Arch. 1994;424:129–34.PubMedGoogle Scholar
  170. 170.
    Cooper CA, Carey FA, Bubb VJ, et al. The pattern of K-ras mutation in pulmonary adenocarcinoma defines a new pathway of tumour development in the human lung. J Pathol. 1997;181:401–4.PubMedGoogle Scholar
  171. 171.
    Westra WH, Baas IO, Hruban RH, et al. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res. 1996;56:2224–8.PubMedGoogle Scholar
  172. 172.
    Jackson EL, Willis N, Mercer K, et al. Analysis of lung tumour initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001;15:3243–8.PubMedGoogle Scholar
  173. 173.
    Sasaki H, Hikosaka Y, Kawano O, et al. Evaluation of Kras gene mutation and copy number gain in non-small cell lung cancer. J Thorac Oncol. 2011;6: 15–20.PubMedGoogle Scholar
  174. 174.
    Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Can Res. 2007;13:2890–6.Google Scholar
  175. 175.
    Chiosea S, Shuai Y, Cieply K, et al. EGFR fluorescence in situ hybridization-positive lung adenocarcinoma: incidence of coexisting KRAS and BRAF mutations. Hum Pathol. 2010;41:1053–60.PubMedGoogle Scholar
  176. 176.
    Janmaat ML, Rodriguez JA, Gallegos-Ruiz M, et al. Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer. 2006;118:209–14.PubMedGoogle Scholar
  177. 177.
    Shepherd FA, Tsao MS. Epidermal growth factor receptor biomarkers in non-small-cell lung cancer: a riddle, wrapped in a mystery, inside an enigma. J Clin Oncol. 2010;28:903–5.PubMedGoogle Scholar
  178. 178.
    Vakiani E, Solit DB. KRAS and BRAF: drug targets and predictive biomarkers. J Pathol. 2011;223:219–29.PubMedGoogle Scholar
  179. 179.
    Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997–7000.PubMedGoogle Scholar
  180. 180.
    Naoki K, Chen TH, Richards WG, et al. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 2002;62:7001–3.PubMedGoogle Scholar
  181. 181.
    Sasaki H, Kawano O, Endo K, et al. Uncommon V599E BRAF mutations in Japanese patients with lung cancer. J Surg Res. 2006;133:203–6.PubMedGoogle Scholar
  182. 182.
    Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signalling pathway in lung cancers. Int J Cancer. 2006;118:257–62.PubMedGoogle Scholar
  183. 183.
    Yousem SA, Nikiforova M, Nikiforov Y. The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol. 2008;32:1317–21.PubMedGoogle Scholar
  184. 184.
    De Oliveira Duarte Achcar R, Nikiforova MN, Yousem S. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol. 2009;131: 694–700Google Scholar
  185. 185.
    Pratilas CA, Hanrahan AJ, Halilovic E, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 2008;68:9375–83.PubMedGoogle Scholar
  186. 186.
    Marcus AI, Zhou W. LKB1 regulated pathways in lung cancer invasion and metastasis. J Thorac Oncol. 2010;5:1883–6.PubMedGoogle Scholar
  187. 187.
    Ji H, Ramsey MR, Hayes DN, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007;448:807–10.PubMedGoogle Scholar
  188. 188.
    Sanchez-Cespedes M, Parrella P, Esteller M, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002;62: 3659–62.PubMedGoogle Scholar
  189. 189.
    Gao B, Sun Y, Zhang J, et al. Spectrum of LKI1, EGFR, and KRAS mutations in Chinese lung adenocarcinomas. J Thorac Oncol. 2010;5:1130–5.PubMedGoogle Scholar
  190. 190.
    Okuda K, Sasaki H, Hikosaka Y, et al. LKB1 gene alterations in surgically resectable adenocarcinoma of the lung. Surg Today. 2011;41:107–10.PubMedGoogle Scholar
  191. 191.
    Onozato R, Kosaka T, Achiwa H, et al. LKB1 gene mutations in Japanese lung cancer patients. Cancer Sci. 2007;98:1747–51.PubMedGoogle Scholar
  192. 192.
    Ghaffar H, Sahin F, Sanchez-Cepedes M, et al. LKB1 protein expression in the evolution of glandular neoplasia of the lung. Clin Cancer Res. 2003;9:2998–3003.PubMedGoogle Scholar
  193. 193.
    Fernandez P, Carretero J, Medina PP, et al. Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations. Oncogene. 2004;23:5084–91.PubMedGoogle Scholar
  194. 194.
    Fan D, Ma C, Zhang H. The molecular mechanisms that underlie the tumor suppressor function of LKB1. Acta Biochim Biophys Sin (Shanghai). 2009;41:97–107.Google Scholar
  195. 195.
    Mahoney CL, Choudhury B, Davies H, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer. 2009;100:370–5.PubMedGoogle Scholar
  196. 196.
    Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 2009;420:345–61.PubMedGoogle Scholar
  197. 197.
    Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 2009;27:4232–5.PubMedGoogle Scholar
  198. 198.
    Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 2008;68:4971–6.PubMedGoogle Scholar
  199. 199.
    Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15:3143–9.PubMedGoogle Scholar
  200. 200.
    Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small cell lung cancer who harbour EML4-ALK. J Clin Oncol. 2009;27:4247–53.PubMedGoogle Scholar
  201. 201.
    Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harbouring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res. 2010;16:5581–90.PubMedGoogle Scholar
  202. 202.
    Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumour lung tissues. Am J Pathol. 2009;174: 661–70.PubMedGoogle Scholar
  203. 203.
    Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF1 cell lineage, an acinar histology and young onset. Mod Pathol. 2009;22:508–15.PubMedGoogle Scholar
  204. 204.
    Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14:6618–24.PubMedGoogle Scholar
  205. 205.
    Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14: 4275–83.PubMedGoogle Scholar
  206. 206.
    Wong D, Leung E, So K, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from non-smokers with wild-type EGFR and KRAS. Cancer. 2009;115:1723–33.PubMedGoogle Scholar
  207. 207.
    Paik JH, Choe G, Kim H, et al. Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell cancer. Correlation with fluorescence in situ hybridization. J Thorac Oncol. 2011;6:466–72.PubMedGoogle Scholar
  208. 208.
    Yi ES, Boland JM, Maleszewski JJ, et al. Correlation of immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol. 2011;6: 459–65.PubMedGoogle Scholar
  209. 209.
    Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements. A new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4:1450–4.PubMedGoogle Scholar
  210. 210.
    Sozzi G, Martelli MP, Conte D, et al. The EML4-ALK transcript but not the fusion protein can be expressed in reactive and neoplastic lymphoid tissues. Haematologica. 2009;94:1307–11.PubMedGoogle Scholar
  211. 211.
    Mano H, Takeuchi K. EML4-ALK fusion in lung. Am J Pathol. 2010;176:1552–3.PubMedGoogle Scholar
  212. 212.
    Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. New Engl J Med. 2010;363:1693–703.PubMedGoogle Scholar
  213. 213.
    Perner S, Wagner PL, Demichelis F, et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia. 2008;10:298–302.PubMedGoogle Scholar
  214. 214.
    Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152–8.PubMedGoogle Scholar
  215. 215.
    Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathological features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15:5216–23.PubMedGoogle Scholar
  216. 216.
    Mino-Kenudson M, Chirieac LR, Law K, et al. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res. 2010;16:1561–71.PubMedGoogle Scholar
  217. 217.
    Bean J, Brennan C, Shih J-Y, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumours with acquired resistance to gefitinib or erlotinib. PNAS. 2007;104:20932–7.PubMedGoogle Scholar
  218. 218.
    Onozato R, Kosaka T, Kuwano H, et al. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol. 2009;4: 5–11.PubMedGoogle Scholar
  219. 219.
    Beau-Faller M, Ruppert AM, Voegeli AC, et al. MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naive cohort. J Thorac Oncol. 2008;3:331–9.PubMedGoogle Scholar
  220. 220.
    Matsubara D, Ishikawa S, Sachiko O, et al. Co-activation of epidermal growth factor receptor and c-MET defines a distinct subset of lung adenocarcinomas. Am J Pathol. 2010;177:2191–204.PubMedGoogle Scholar
  221. 221.
    Nakamura Y, Niki T, Goto A, et al. C-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci. 2007;98:1006–13.PubMedGoogle Scholar
  222. 222.
    Onitsuka T, Uramoto H, Ono K, et al. 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. 2010;5:591–6.PubMedGoogle Scholar
  223. 223.
    Marks JL, Gong Y, Chitale D, et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signalling pathway genes in lung adenocarcinoma. Cancer Res. 2008;68:5524–8.PubMedGoogle Scholar
  224. 224.
    Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res. 2008;68:6913–21.PubMedGoogle Scholar
  225. 225.
    Nana-Sinkam SP, Fabbri M, Croce CM. MicroRNAs in cancer: personalizing diagnosis and therapy. Ann N Y Acad Sci. 2010;1210:25–33.PubMedGoogle Scholar
  226. 226.
    Lin PY, Yu SL, Yang PC. MicroRNA in lung cancer. Br J Cancer. 2010;103:1144–8.PubMedGoogle Scholar
  227. 227.
    Wu X, Piper-Hunter MG, Crawford M, et al. MicroRNAS in the pathogensis of lung cancer. J Thorac Oncol. 2009;4:1028–34.PubMedGoogle Scholar
  228. 228.
    Du L, Pertsemlidis A. MicroRNAs and lung cancer: tumours and 22-mers. Cancer Met Rev. 2010;29: 109–22.Google Scholar
  229. 229.
    Mallick R, Patnaik SK, Yendamuri S. MicroRNAs and lung cancer: biology and applications in diagnosis and prognosis. J Carcinog. 2010;9:8.PubMedGoogle Scholar
  230. 230.
    Osada H, Takahashi T. let-7 and miR-17-92: small-sized major players in lung cancer development. Cancer Sci. 2011;102:9–17.PubMedGoogle Scholar
  231. 231.
    Yu L, Todd NW, Xing L et al. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer 2010;127:2870–2878.Google Scholar
  232. 232.
    Landi MT, Zhae Y, Rotunno M, et al. MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res. 2010;16: 430–41.PubMedGoogle Scholar
  233. 233.
    Lebanony D, Benjamin H, Gilad S, et al. Diagnostic assay based on has-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol. 2009;27:2030–7.PubMedGoogle Scholar
  234. 234.
    Bishop JA, Benjamin H, Cholakh H, et al. Accurate classification of non-small cell lung carcinoma using a novel microRNA-based approach. Clin Can Res. 2010;16:610–9.Google Scholar
  235. 235.
    Chiosea S, Jelezcova E, Chandran U, et al. Overexpression of Dicer in precursor lesions in lung adenocarcinoma. Cancer Res. 2007;67:2345–50.PubMedGoogle Scholar
  236. 236.
    Seike M, Goto A, Okano T, et al. MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci U S A. 2009;106:12085–90.PubMedGoogle Scholar
  237. 237.
    Cho WC, Chow AS, Au JS. MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1. RNA Biol. 2011;8(1): 125–31.PubMedGoogle Scholar
  238. 238.
    Dacic S, Kelly L, Shuai Y, et al. miRNA expression profiling of lung adenocarcinomas: correlation with mutational status. Mod Pathol. 2010;23:1577–82.PubMedGoogle Scholar
  239. 239.
    Hatley ME, Patrick DM, Garcia MR, et al. Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell. 2010;18:282–93.PubMedGoogle Scholar
  240. 240.
    Chou YT, Lin HH, Lien YC, Wang YH, et al. EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer Res. 2010;70:8822–31.PubMedGoogle Scholar
  241. 241.
    Roybal JD, Zang Y, Ahn YH, et al. miR-200 Inhibits lung adenocarcinoma cell invasion and metastasis by targeting Flt1/VEGFR1. Mol Cancer Res. 2011;9:25–35.PubMedGoogle Scholar
  242. 242.
    Nelson HH, Christensen BC, Plaza SL, et al. KRAS mutation, KRAS-LCS6 polymorphism, and non-small cell lung cancer. Lung Cancer. 2010;69:51–3.PubMedGoogle Scholar
  243. 243.
    Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004;64:3753–6.PubMedGoogle Scholar
  244. 244.
    Inamura K, Togashi Y, Nomura K, et al. Let-7 microRNA expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosis. Lung Cancer. 2007;58: 392–6.PubMedGoogle Scholar
  245. 245.
    Voortram J, Goto A, Mediboure J, et al. MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. Cancer Res. 2010;70:8288–98.Google Scholar
  246. 246.
    Heller G, Zielinski CC, Zochbauer-Muller S. Lung cancer: from single-gene methylation to methylome profiling. Cancer Met Rev. 2010;29:95–107.Google Scholar
  247. 247.
    Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3:253–66.PubMedGoogle Scholar
  248. 248.
    Kerr KM, Galler JS, Hagen JA, et al. The role of DNA methylation in the development and progression of lung adenocarcinoma. Dis Markers. 2007;23: 5–30.PubMedGoogle Scholar
  249. 249.
    Tsou JA, Hagen JA, Carpenter CL, et al. DNA methylation analysis: a powerful new tool for lung cancer diagnosis. Oncogene. 2002;21:5450–61.PubMedGoogle Scholar
  250. 250.
    Virmani AK, Tsou JA, Siegmund KD, et al. Hierarchical clustering of lung cancer cell lines using DNA methylation markers. Cancer Epidemiol Biomarkers Prev. 2002;11:291–7.PubMedGoogle Scholar
  251. 251.
    Tsou JA, Shen LY, Siegmund KD, et al. Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. Lung Cancer. 2005;47:193–204.PubMedGoogle Scholar
  252. 252.
    Tsou JA, Galler JS, Siegmund KD, et al. Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma. Mol Cancer. 2007;6:70.PubMedGoogle Scholar
  253. 253.
    Divine KK, Pulling LC, Marron-Terada PG, et al. Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers. Int J Cancer. 2005;114:400–5.PubMedGoogle Scholar
  254. 254.
    Selamat SA, Galler JS, Joshi AD, et al. DNA methylation changes in atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, and lung adenocarcinoma. PLoS One. 2011;6(6):e21443.PubMedGoogle Scholar
  255. 255.
    Chilosi M, Murer B. Mixed adenocarcinomas of the lung. place in new proposals in classification, mandatory for target therapy. Arch Pathol Lab Med. 2010;134:55–65.PubMedGoogle Scholar
  256. 256.
    Inamura K, Ninomiya H, Ishikawa Y, et al. Is the epidermal growth factor receptor status in lung cancers reflected in clinicopathological features? Arch Pathol Lab Med. 2010;134:66–72.PubMedGoogle Scholar
  257. 257.
    Sholl LM, Yeap BY, Iafrate AJ, et al. Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never smokers. Cancer Res. 2009;69:8341–8.PubMedGoogle Scholar
  258. 258.
    Ninomiya H, Hiramatsu M, Inamura K, et al. Correlation between morphology and EGFR mutations in lung adenocarcinomas. Significance of the micropapillary pattern and the hobnail cell type. Lung Cancer. 2009;63:235–40.PubMedGoogle Scholar
  259. 259.
    Marchetti A, Buttitta F, Pellegrini S, et al. Bronchioloalveolar lung carcinomas: K-ras mutations are constant events in the mucinous subtype. J Pathol. 1996;179:254–9.PubMedGoogle Scholar
  260. 260.
    Finberg KE, Sequist LV, Joshi VA, et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn. 2007;9:320–6.PubMedGoogle Scholar
  261. 261.
    Ang DC, Zakowski MF, Ladanyi M, et al. Characteristic morphology and immunoprofile of lung adenocarcinoma with KRAS mutations: propensity for solid growth pattern and correlation with TTF-1 expression. Mod Pathol. 2010;23(Suppl):396A.Google Scholar
  262. 262.
    Kerr KM, Barr R. Unpublished data.Google Scholar
  263. 263.
    Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008;3:13–7.PubMedGoogle Scholar
  264. 264.
    Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol. 2010;17:889–97.PubMedGoogle Scholar
  265. 265.
    Jokoji R, Yamasaki T, Minami S, et al. Combination of morphological feature analysis and immunohistochemistry is useful for screening of EML4-ALK-positive lung adenocarcinoma. J Clin Pathol. 2010;63:1066–70.PubMedGoogle Scholar
  266. 266.
    Ishikawa Y. Personal communication. June 29, 2010.Google Scholar
  267. 267.
    Kaufmann O, Dietel M. Thyroid transcription factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B. Histopathology. 2000;36:8–16.PubMedGoogle Scholar
  268. 268.
    Stenhouse G, Fyfe N, King G, et al. Thyroid transcription factor 1 in pulmonary adenocarcinoma. J Clin Pathol. 2004;57:383–7.PubMedGoogle Scholar
  269. 269.
    Pelosi G, Fraggetta F, Pasini F, et al. Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung. Am J Surg Pathol. 2001;25:363–72.PubMedGoogle Scholar
  270. 270.
    Tang X, Kadara H, Behrens C, et al. Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: implications in lung cancer pathogenesis and prognosis. Clin Cancer Res. 2011;17(8):2434–43.PubMedGoogle Scholar
  271. 271.
    Loo PS, Thomas SC, Nicolson MC, et al. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol. 2010;5:442–7.PubMedGoogle Scholar
  272. 272.
    Inamura K, Satoh Y, Okumura S, et al. Pulmonary adenocarcinomas with enteric differentiation: ­histological and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas. Am J Surg Pathol. 2005;29:660–5.PubMedGoogle Scholar
  273. 273.
    Hirano T, Gong Y, Yoshida K, et al. Usefulness of TA02 (napsin A) to distinguish primary lung adenocarcinoma from metastatic lung adenocarcinoma. Lung Cancer. 2003;41:155–62.PubMedGoogle Scholar
  274. 274.
    Bishop JA, Sharma R, Illei PB. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol. 2010;41: 20–5.PubMedGoogle Scholar
  275. 275.
    Suzuki A, Shijubo N, Yamada G, et al. Napsin A is useful to distinguish primary lung adenocarcinoma from adenocarcinomas of other organs. Pathol Res Pract. 2005;201:579–86.PubMedGoogle Scholar
  276. 276.
    Mukhopadhyay S, Katzenstein AL. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am J Surg Pathol. 2011;35:15–25.PubMedGoogle Scholar
  277. 277.
    Rossi G, Murer B, Cavazza A, et al. Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathological and immunohistochemical study with special reference to CDX2 homeobox gene and MUC2 expression. Am J Surg Pathol. 2004;28: 442–52.PubMedGoogle Scholar
  278. 278.
    Yatabe Y, Koga T, Mitsudomi T, Takahashi T. CK20 expression, CDX2 expression, K-ras mutation and goblet cell morphology in a subset of lung adenocarcinomas. J Pathol. 2004;203:645–52.PubMedGoogle Scholar
  279. 279.
    Mazziotta RM, Borczuk AC, Powell CA, Mansukhani M. CDX2 immunostaining as a gastrointestinal marker: expression in lung carcinomas is a potential pitfall. Appl Immunohistochem Mol Morphol. 2005;13:55–60.PubMedGoogle Scholar
  280. 280.
    Yousem SA. Pulmonary intestinal-type adenocarcinoma does not show enteric differentiation by immunohistochemical study. Mod Pathol. 2005;18:816–21.PubMedGoogle Scholar
  281. 281.
    Kerr KM. Current issues in pulmonary adenocarcinoma. Diagn Histopathol. 2008;14:509–18.Google Scholar
  282. 282.
    Chapman AD, Kerr KM. The association between atypical adenomatous hyperplasia and primary lung cancer. Br J Cancer. 2000;83:632–6.PubMedGoogle Scholar
  283. 283.
    Gazdar AF, Minna JD. Multifocal lung cancers—clonality vs field cancerization and does it matter? J Natl Cancer Inst. 2009;101:541–3.PubMedGoogle Scholar
  284. 284.
    Girard N, Ostrovnaya I, Lau C, et al. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res. 2009;15:5184–90.PubMedGoogle Scholar
  285. 285.
    Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33:1752–64.PubMedGoogle Scholar
  286. 286.
    Cagle PT, Allen TC, Dacic S, et al. Revolution in lung cancer. new challenges for the surgical pathologist. Arch Pathol Lab Med. 2011;135:110–6.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Pathology, Aberdeen Royal InfirmaryAberdeen University Medical SchoolAberdeenUK

Personalised recommendations