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The clinicopathological significance of ALK rearrangements and KRAS and EGFR mutations in primary pulmonary mucinous adenocarcinoma

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Tumor Biology

Abstract

Primary pulmonary mucinous adenocarcinoma (PPMA) is one of the important subtypes of lung adenocarcinoma. Detection of anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements and of KRAS and epidermal growth factor receptor (EGFR) mutations will help in diagnosing and predicting treatment outcome. The aim of this study was to investigate the clinicopathological significance of ALK rearrangements, KRAS and EGFR mutations in PPMA. ALK expression was detected immunohistochemically. KRAS and EGFR mutations were determined by the amplification refractory mutation system. Seventy-three patients of PPMA were enrolled. ALK rearrangements were detected in 34.2 % of patients and were more frequent in upper/middle lobe, stage III-IV, lymphatic permeation-positive patients and non-smokers. ALK rearrangements were significantly increased in the solid tumor predominant with mucin production subtype, and in special tissue structures, including signet ring cells, cribriform, and micropapillary patterns. KRAS mutations were observed in 23.3 % of patients and were more prevalent in invasive mucinous adenocarcinoma and lower lobe tumors. Only one case of ALK rearrangements harbored KRAS mutation, and no cases manifested with the coexistence of ALK rearrangements and EGFR mutations. KRAS and EGFR co-mutation was detected in one case. PPMA patients with ALK rearrangements or KRAS mutation represent a unique subtype in NSCLC. The results provide basis data for target therapy screening of PPMA patients.

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References

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Mansuet-Lupo A, Bobbio A, Blons H, et al. The new histologic classification of lung primary adenocarcinoma subtypes is a reliable prognostic marker and identifies tumors with different mutation status: the experience of a French cohort. Chest. 2014;146:633–43.

    Article  PubMed  Google Scholar 

  3. SambrookGowar FJ. An unusual mucous cyst of the lung. Thorax. 1978;33:796–9.

    Article  CAS  Google Scholar 

  4. Kragel PJ, Devaney KO, Meth BM, et al. Mucinous cystadenoma of the lung. A report of two cases with immunohistochemical and ultrastructural analysis. Arch Pathol Lab Med. 1990;114:1053–6.

    CAS  PubMed  Google Scholar 

  5. Gaikwad A, Gupta A, Hare S, et al. Primary adenocarcinoma of lung: a pictorial review of recent updates. Eur J Radiol. 2012;81:4146–55.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Antonoff MB, D’Cunha J. Non-small cell lung cancer: the era of targeted therapy. Lung Cancer. 2012;3:31–41.

    PubMed  PubMed Central  Google Scholar 

  8. Parums DV. Current status of targeted therapy in non-small cell lung cancer. Drugs Today. 2014;50:503–25.

    Article  CAS  PubMed  Google Scholar 

  9. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29:2121–7.

    Article  PubMed  Google Scholar 

  10. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. Plos Med. 2005;2:e17.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900–9.

    Article  CAS  PubMed  Google Scholar 

  12. Hata A, Katakami N, Fujita S, et al. Frequency of EGFR and KRAS mutations in Japanese patients with lung adenocarcinoma with features of the mucinous subtype of bronchioloalveolar carcinoma. J Thorac Oncol. 2010;5:1197–200.

    Article  PubMed  Google Scholar 

  13. Kakegawa S, Shimizu K, Sugano M, et al. Clinicopathological features of lung adenocarcinoma with KRAS mutations. Cancer. 2011;117:4257–66.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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 ThoracOncol. 2009;4:1450–4.

    Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. Bang Y-J. The potential for crizotinib in non-small cell lung cancer: a perspective review. Ther Adv Med Oncol. 2011;3:279–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nishino M, Klepeis VE, Yeap BY, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol. 2012;25:1462–72.

    Article  CAS  PubMed  Google Scholar 

  19. Yoshida A, Tsuta K, Nakamura H, et al. Comprehensive histologic analysis of ALK-rearranged lung carcinomas. Am J Surg Pathol. 2011;35:1226–34.

    Article  PubMed  Google Scholar 

  20. Gainor JF, Varghese AM, Ou S-HI, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19:4273–81.

    Article  CAS  PubMed  Google Scholar 

  21. Wong DW-S, Leung EL-H, So KK-T, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115:1723–33.

    Article  CAS  PubMed  Google Scholar 

  22. Conde E, Suárez-Gauthier A, Benito A, et al. Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry. PLoS One. 2014;9:e107200.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Minca EC, Portier BP, Wang Z, et al. ALK status testing in non-small cell lung carcinoma: correlation between ultrasensitive IHC and FISH. J Mol Diagn. 2013;15:341–6.

    Article  CAS  PubMed  Google Scholar 

  24. Liu Y, Liu B, Li X-Y, et al. A comparison of ARMS and direct sequencing for EGFR mutation analysis and tyrosine kinase inhibitors treatment prediction in body fluid samples of non-small-cell lung cancer patients. J Exp Clin Cancer Res. 2011;30:111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol. 2009;22:508–15.

    Article  CAS  PubMed  Google Scholar 

  27. Kim H, Jang SJ, Chung DH, et al. A comprehensive comparative analysis of the histomorphological features of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations: frequent expression of epithelial–mesenchymal transition markers than other genotype. PLoS One. 2013;8:e76999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang Y, Li J, Wang R, et al. The prognostic and predictive value of solid subtype in invasive lung adenocarcinoma. Sci Rep. 2014;4:7163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Choi IH, Lee B, Han J, et al. Micropapillary mucinous adenocarcinoma of the lung: a brief case report. Korean J Pathol. 2013;47:603–5.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tam IY-S, Chung L-P, 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.

    Article  CAS  PubMed  Google Scholar 

  31. Rodenhuis S, van de Wetering ML, Mooi WJ, et al. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med. 1987;317:929–35.

    Article  CAS  PubMed  Google Scholar 

  32. Wislez M, Antoine M, Baudrin L, et al. Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib. Lung Cancer. 2010;68:185–91.

    Article  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kadota K, Yeh Y-C, D’Angelo SP, et al. Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: invasive mucinous pattern and extracellular mucin are associated with KRAS mutation. Am J Surg Pathol. 2014;38:1118–27.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol. 2009;174:661–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Magor Programs of Beijing Municipal Science and Technology Commission (D141100000214003).

Conceived and designed the experiments: Haiqing Zhang, Lixin Wei, and Yang Qu. Performed the experiments: Yang Qu and Nanying Che. Analyzed the data: Yang Qu, Nanying Che, and Dan Zhao. Contributed reagents/materials/analysis tools: Chen Zhang, Dan Shu, and Lijuan Zhou. Wrote the paper: Yang Qu. Collecting data: Lili zhang, Chongli Wang, Li Zhang, and Chunling Yin.

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    Authors and Affiliations

    1. Department of Pathology, The General Hospital of People’s Liberation Army, 28# Fuxing Road, Haidian District, Beijing, 100853, China

      Yang Qu & Lixin Wei

    2. Department of Pathology, Beijing Chest Hospital, Capital Medical University, 97# Machang, Tongzhou District, Beijing, 101149, China

      Yang Qu, Nanying Che, Dan Zhao, Chen Zhang, Dan Su, Lijuan Zhou, Lili Zhang, Chongli Wang & Haiqing Zhang

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    1. Yang Qu
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    3. Dan Zhao
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    Correspondence to Haiqing Zhang or Lixin Wei.

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    Yang Qu and Nanying Che contributed equally to this work.

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    Qu, Y., Che, N., Zhao, D. et al. The clinicopathological significance of ALK rearrangements and KRAS and EGFR mutations in primary pulmonary mucinous adenocarcinoma. Tumor Biol. 36, 6417–6424 (2015). https://doi.org/10.1007/s13277-015-3331-4

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    • DOI: https://doi.org/10.1007/s13277-015-3331-4

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