Skip to main content
Log in

Analysis of Driver Mutations in Female Non-Smoker Asian Patients with Pulmonary Adenocarcinoma

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Previous studies have revealed that EGFR mutation and/or EML4–ALK gene fusion rate was higher in the non-smoker Asian females with pulmonary adenocarcinoma. The aim of this study is to determine the distribution of known oncogenic driver mutations in the female non-smoker Asian patients with pulmonary adenocarcinoma. 104 consecutively resected lung adenocarcinomas from 396 non-smoker females (less than 100 cigarettes in a lifetime) at a single institution (Tongji University, Shanghai, China) were analyzed for mutations in EGFR, EML4−ALK, KRAS, HER2, BRAF, and PIK3CA. 73 (70.2 %) tumors harbored EGFR mutations; among these, 28 were deletions in exon 19, 44 were L858R missense changes, and eight were T790M mutations. 10 (9.6 %) harbored EML4−ALK fusions, two harbored KRAS mutations, two harbored BRAF mutations, and two harbored PI3K mutations. A majority of the mutations were mutually exclusive, except two with EGFR mutation and BRAF mutation, one with EML4−ALK fusions and PI3K mutation. Thus, 82.7 % (86 of 104; 95 % CI, 75.4–90.0 %) of lung adenocarcinomas from non-smoker females were found to harbor the well-known oncogenic mutations in five genes. Lung cancer in non-smoking Asian females is a distinct entity, with majority of this subgroup being developed by the oncogenic mutations. The prospective mutation examination in this population will be helpful for devising a targeted therapy for a majority of the patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Siegel, R., Ward, E., Brawley, O., & Jemal, A. (2011). Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal for Clinicians, 61, 212–236.

    Article  Google Scholar 

  2. Samet, J. M. (2004). Adverse effects of smoke exposure on the upper airway. Tobacco Control, 13(Suppl 1), i57–i60.

    Article  PubMed  Google Scholar 

  3. Samet, J. M., Avila-Tang, E., Boffetta, P., Hannan, L. M., Olivo-Marston, S., et al. (2009). Lung cancer in never smokers: Clinical epidemiology and environmental risk factors. Clinical Cancer Research, 15, 5626–5645.

    Article  PubMed  Google Scholar 

  4. Thatcher, N., Chang, A., Parikh, P., Rodrigues Pereira, J., Ciuleanu, T., et al. (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 366, 1527–1537.

    Article  PubMed  CAS  Google Scholar 

  5. Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 350, 2129–2139.

    Article  PubMed  CAS  Google Scholar 

  6. Mok, T. S., Wu, Y. L., Thongprasert, S., Yang, C. H., Chu, D. T., et al. (2009). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. New England Journal of Medicine, 361, 947–957.

    Article  PubMed  CAS  Google Scholar 

  7. Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., et al. (2010). Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. New England Journal of Medicine, 362, 2380–2388.

    Article  PubMed  CAS  Google Scholar 

  8. Rosell, R., Gervais, R., & Vergnenegre, A. (2011). Spanish Lung Cancer Group. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European erlotinib versus chemotherapy (EURTAC) phase III randomized trial. Journal Clinical Oncology, 29, 7503.

    Google Scholar 

  9. Zhou, C. C., Wu, Y. L., Chen, G. Y., Feng, J. F., Liu, X. Q., et al. (2011). Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncology, 12, 735–742.

    Article  PubMed  CAS  Google Scholar 

  10. Ettinger, D. S., Akerley, W., Bepler, G., Blum, M. G., Chang, A., et al. (2010). Non-small cell lung cancer. Journal of National Comprehensive Cancer Network, 8, 740–801.

    CAS  Google Scholar 

  11. Shaw, A. T., Yeap, B. Y., Mino-Kenudson, M., Digumarthy, S. R., Costa, D. B., et al. (2009). Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4−ALK. Journal Clinical Oncology, 27, 4247–4253.

    Article  CAS  Google Scholar 

  12. .Bang, Y., & Al, E. (2010). Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC). Journal of Clinical Oncology, 28.

  13. Gadgeel, S. M., & Bepler, G. (2011). Crizotinib: An anaplastic lymphoma kinase inhibitor. Future Oncology, 7, 947–953.

    Article  PubMed  CAS  Google Scholar 

  14. Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., et al. (2007). Characterizing the cancer genome in lung adenocarcinoma. Nature, 450, 893–898.

    Article  PubMed  CAS  Google Scholar 

  15. Zhou, C. C., Ren, S. X., Zhou, S. W., Zhang, L., Xu, J. F., et al. (2010). High-level mRNA of excision repair cross-complementation group 1 gene is associated with poor outcome of platinum-based doublet chemotherapy of advanced nonsmall cell lung cancer patients. Cancer Investigation, 28, 1078–1083.

    Article  PubMed  Google Scholar 

  16. Wilson, R. K., Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., et al. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature, 455, 1069–1075.

    Article  PubMed  Google Scholar 

  17. Rikova, K., Guo, A., Zeng, Q., Possemato, A., Yu, J., et al. (2007). Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell, 131, 1190–1203.

    Article  PubMed  CAS  Google Scholar 

  18. Simon, R., & Youn, A. (2011). Identifying cancer driver genes in tumor genome sequencing studies. Bioinformatics, 27, 175–181.

    Article  PubMed  Google Scholar 

  19. Carvajal, R. D., Antonescu, C. R., Wolchok, J. D., Chapman, P. B., Roman, R. A., et al. (2011). KIT as a therapeutic target in metastatic melanoma. JAMA, the Journal of the American Medical Association, 305, 2327.

    Article  CAS  Google Scholar 

  20. Cantley, L. C., Engelman, J. A., Chen, L., Tan, X. H., Crosby, K., et al. (2008). Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Medicine, 14, 1351–1356.

    Article  PubMed  Google Scholar 

  21. Pao, W., & Girard, N. (2011). New driver mutations in non-small-cell lung cancer. Lancet Oncology, 12, 175–180.

    Article  PubMed  CAS  Google Scholar 

  22. Pao, W., Balak, M., Riely, G., Li, A., Zakowski, M., et al. (2006). Molecular analysis of NSCLC patients with acquired resistance to gefitinib or erlotinib. Journal of Clinical Oncology, 24, 7078.

    Google Scholar 

  23. Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., et al. (2005). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine, 2, e73.

    Article  PubMed  Google Scholar 

  24. Fukuoka, M., Wu, Y.L., Thongprasert, S., Sunpaweravong, P., & Leong, S.S., et al. (2011). Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia (IPASS). Journal of Clinical Oncology.

  25. Zhou, Q., Zhang, X. C., Chen, Z. H., Yin, X. L., Yang, J. J., et al. (2011). Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. Journal of Clinical Oncology, 29, 3316–3321.

    Article  PubMed  CAS  Google Scholar 

  26. Huang, S. F., Wu, C. C., Hsu, H. Y., Liu, H. P., Chang, J. W. C., et al. (2008). Reversed mutation rates of KRAS and EGFR genes in adenocarcinoma of the lung in Taiwan and their implications. Cancer, 113, 3199–3208.

    Article  PubMed  Google Scholar 

  27. Chen, H. Q., Sun, Y. H., Ren, Y., Fang, Z. Y., Li, C. G., et al. (2010). Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. Journal of Clinical Oncology, 28, 4616–4620.

    Article  PubMed  Google Scholar 

  28. Kris, M., Johnson, B., & Kwiatkowski, D. (2011). Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s lung cancer mutation consortium (LCMC).

Download references

Acknowledgments

This study was supported by the Amory Company and partially supported by grants from the key project of the Science and Technology Commission of Shanghai Municipality (No. 06DZ19502).

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Caicun Zhou.

Additional information

S Ren and P Kuang contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ren, S., Kuang, P., Zheng, L. et al. Analysis of Driver Mutations in Female Non-Smoker Asian Patients with Pulmonary Adenocarcinoma. Cell Biochem Biophys 64, 155–160 (2012). https://doi.org/10.1007/s12013-012-9384-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-012-9384-8

Keywords

Navigation