Skip to main content

Advertisement

SpringerLink
Log in

The relationship between EGFR gain and VHL loss in lung adenocarcinoma and poor patient survival

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

The prognosis of lung cancer remains poor and clinically applicable prognostic markers have not yet been satisfactory identified. Several chromosomal copy number alterations (CNAs) have been associated with metastasis, relapse, and survival of patients with lung cancer; however, no study has focused exclusively on identifying CNAs at a gene level. The aim of this study was to identify genes whose CNAs are associated with survival of patients with lung adenocarcinoma.

Methods

The CNA status of a panel of 48 genes was detected by high-resolution array comparative genomic hybridization in 56 lung adenocarcinoma samples. The follow-up time of these patients was 8.5–65.7 months. The gene CNAs were analyzed for their association with patient survival.

Results

Cox univariate regression analysis revealed that EGFR gain (hazard ratio (HR) 3.84, 95% confidence interval (CI) 1.62–9.10), VHL loss (HR 4.56, 95% CI 1.85–11.27) and WWOX loss (HR 4.14, 95% CI 1.60–10.69) were each associated with poor survival. Multivariate analyses including EGFR gain, VHL loss and WWOX loss, as well as the clinicopathological variables such as age, sex, tumor size, tumor differentiation and TNM stage showed that EGFR gain (HR 4.63, 95% CI 1.69–12.7) and VHL loss (HR 4.82, 95% CI 1.41–16.43) were independent prognostic factors for poor survival, whereas WWOX loss lost statistical significance.

Conclusion

These findings suggest that EGFR gain and VHL loss are associated with poor overall survival for lung adenocarcinoma patients and may be used as prognostic markers.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lockwood WW, Chari R, Coe BP et al (2010) Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. PLoS Med 7:e1000315

    Article  PubMed  Google Scholar 

  2. Aggarwal C, Somaiah N, Simon GR (2010) Biomarkers with predictive and prognostic function in non-small cell lung cancer: ready for prime time? J Natl Compr Canc Netw 8:822–832

    PubMed  CAS  Google Scholar 

  3. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  4. Sun Z, Aubry MC, Deschamps C et al (2006) Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases. J Thorac Cardiovasc Surg 131:1014–1020

    Article  PubMed  Google Scholar 

  5. Mountzios G, Dimopoulos MA, Soria JC et al (2010) Histopathologic and genetic alterations as predictors of response to treatment and survival in lung cancer: a review of published data. Crit Rev Oncol Hematol 75:94–109

    Article  PubMed  Google Scholar 

  6. Bearz A, Berretta M, Cappellani A et al (2010) Biomarkers in lung cancer. Front Biosci (Elite Ed) 2:1099–1104

    Article  Google Scholar 

  7. Speleman F, Kumps C, Buysse K et al (2008) Copy number alterations and copy number variation in cancer: close encounters of the bad kind. Cytogenet Genome Res 123:176–182

    Article  PubMed  CAS  Google Scholar 

  8. Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141

    Article  PubMed  CAS  Google Scholar 

  9. Pinkel D, Albertson DG (2005) Array comparative genomic hybridization and its applications in cancer. Nat Genet 37(Suppl):S11–S17

    Article  PubMed  CAS  Google Scholar 

  10. Wrage M, Ruosaari S, Eijk PP et al (2009) Genomic profiles associated with early micrometastasis in lung cancer: relevance of 4q deletion. Clin Cancer Res 15:1566–1574

    Article  PubMed  CAS  Google Scholar 

  11. Tai AL, Yan WS, Fang Y et al (2004) Recurrent chromosomal imbalances in nonsmall cell lung carcinoma: the association between 1q amplification and tumor recurrence. Cancer 100:1918–1927

    Article  PubMed  Google Scholar 

  12. Boelens MC, Kok K, van der Vlies P et al (2009) Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. Lung Cancer 66:372–378

    Article  PubMed  Google Scholar 

  13. Gallegos Ruiz MI, Floor K, Roepman P et al (2008) Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS One 3:e0001722

    Article  PubMed  Google Scholar 

  14. Kim TM, Yim SH, Lee JS et al (2005) Genome-wide screening of genomic alterations and their clinicopathologic implications in non-small cell lung cancers. Clin Cancer Res 11:8235–8242

    Article  PubMed  CAS  Google Scholar 

  15. Goeze A, Schluns K, Wolf G et al (2002) Chromosomal imbalances of primary and metastatic lung adenocarcinomas. J Pathol 196:8–16

    Article  PubMed  Google Scholar 

  16. Barrett MT, Scheffer A, Ben-Dor A et al (2004) Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc Natl Acad Sci USA 101:17765–17770

    Article  PubMed  CAS  Google Scholar 

  17. Beroukhim R, Mermel CH, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905

    Article  PubMed  CAS  Google Scholar 

  18. Ma C, Quesnelle KM, Sparano A et al (2009) Characterization CSMD1 in a large set of primary lung, head and neck, breast and skin cancer tissues. Cancer Biol Ther 8:907–916

    Article  PubMed  CAS  Google Scholar 

  19. Peralta R, Baudis M, Vazquez G et al (2010) Increased expression of cellular retinol-binding protein 1 in laryngeal squamous cell carcinoma. J Cancer Res Clin Oncol 136:931–938

    Article  PubMed  CAS  Google Scholar 

  20. Savola S, Klami A, Tripathi A et al (2009) Combined use of expression and CGH arrays pinpoints novel candidate genes in Ewing sarcoma family of tumors. BMC Cancer 9:17

    Article  PubMed  Google Scholar 

  21. Threadgill DW, Dlugosz AA, Hansen LA et al (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234

    Article  PubMed  CAS  Google Scholar 

  22. Sibilia M, Wagner EF (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269:234–238

    Article  PubMed  CAS  Google Scholar 

  23. Onn A, Correa AM, Gilcrease M et al (2004) Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer. Clin Cancer Res 10:136–143

    Article  PubMed  CAS  Google Scholar 

  24. Swinson DE, Cox G, O’Byrne KJ (2004) Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer. Br J Cancer 91:1301–1307

    Article  PubMed  CAS  Google Scholar 

  25. Chang JW, Liu HP, Hsieh MH et al (2008) Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: a chromogenic in situ hybridization study of 182 patients. Lung Cancer 61:328–339

    Article  PubMed  Google Scholar 

  26. Gandhi J, Zhang J, Xie Y et al (2009) Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One 4:e4576

    Article  PubMed  Google Scholar 

  27. Varella-Garcia M, Mitsudomi T, Yatabe Y et al (2009) EGFR and HER2 genomic gain in recurrent non-small cell lung cancer after surgery: impact on outcome to treatment with gefitinib and association with EGFR and KRAS mutations in a Japanese cohort. J Thorac Oncol 4:318–325

    Article  PubMed  Google Scholar 

  28. Davidowitz EJ, Schoenfeld AR, Burk RD (2001) VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling. Mol Cell Biol 21:865–874

    Article  PubMed  CAS  Google Scholar 

  29. Pause A, Lee S, Lonergan KM et al (1998) The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci USA 95:993–998

    Article  PubMed  CAS  Google Scholar 

  30. Chitalia VC, Foy RL, Bachschmid MM et al (2008) Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol 10:1208–1216

    Article  PubMed  CAS  Google Scholar 

  31. Mikhaylova O, Ignacak ML, Barankiewicz TJ et al (2008) The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Mol Cell Biol 28:2701–2717

    Article  PubMed  CAS  Google Scholar 

  32. Young AC, Craven RA, Cohen D et al (2009) Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res 15:7582–7592

    Article  PubMed  CAS  Google Scholar 

  33. Cai Q, Robertson ES (2010) Ubiquitin/SUMO modification regulates VHL protein stability and nucleocytoplasmic localization. PLoS One 5:e12636

    Article  Google Scholar 

  34. Peng Z, Shan C, Wang H (2009) Expression of VHL and HIF-1alpha and its clinical significance in the lung cancer tissue. Zhong Nan Da Xue Xue Bao Yi Xue Ban 34:331–334

    PubMed  CAS  Google Scholar 

  35. Shen H, Gao W, Wu YJ et al (2009) Multicolor fluorescence in situ hybridization and comparative genomic hybridization reveal molecular events in lung adenocarcinomas and squamous cell lung carcinomas. Biomed Pharmacother 63:396–403

    Article  PubMed  CAS  Google Scholar 

  36. Yu S, Bittel DC, Kibiryeva N et al (2009) Validation of the Agilent 244K oligonucleotide array-based comparative genomic hybridization platform for clinical cytogenetic diagnosis. Am J Clin Pathol 132:349–360

    Article  PubMed  CAS  Google Scholar 

  37. Adati N, Huang MC, Suzuki T et al (2009) High-resolution analysis of aberrant regions in autosomal chromosomes in human leukemia THP-1 cell line. BMC Res Notes 2:153

    Article  PubMed  Google Scholar 

  38. Staaf J, Jonsson G, Ringner M et al (2010) High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer. Breast Cancer Res 12:R25

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Heilongjiang Science Foundation for Young Scholar (No.QC2009C14).

Conflict of interest

None of the authors have any conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150001, China

    Yushi Zhao, Ye Li, Hongguang Lu, Jianxin Chen & Zhijie Zhang

  2. Department of Thoracic Surgery, The First Affiliated Hospital, Harbin Medical University, No. 23 Youzheng Street, Harbin, 150001, China

    Shengfa Wang

  3. Department of Thoracic Surgery, The Second Affiliated Hospital, Mudanjiang Medical College, Mudanjiang, 157010, China

    Yubin Jin

  4. Department of Oncology, No.113 Hospital of People’s Liberation Army, Ningbo, 315040, China

    Zhong-Zheng Zhu

Authors
  1. Yushi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ye Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shengfa Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongguang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianxin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhijie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yubin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhong-Zheng Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shengfa Wang.

Additional information

Drs. Y. Zhao and Y. Li contributed equally to this work.

About this article

Cite this article

Zhao, Y., Li, Y., Wang, S. et al. The relationship between EGFR gain and VHL loss in lung adenocarcinoma and poor patient survival. Int J Clin Oncol 16, 679–685 (2011). https://doi.org/10.1007/s10147-011-0248-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-011-0248-9

Keywords

Search

Navigation