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Comparison of p53 and Epidermal Growth Factor Receptor Gene Status Between Primary Tumors and Lymph Node Metastases in Non-Small Cell Lung Cancers

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

To obtain insight into the cancer progression and metastatic process, we evaluate p53/epidermal growth factor receptor (EGFR) somatic aberrations in non-small-cell lung cancers to compare accumulated genetic alterations between primary tumors and lymph node metastases.

Materials and Methods

A total of 56 primary lung cancers with corresponding lymph node metastases were identified to investigate somatic mutations and altered expressions of p53 and EGFR for clonality assessment. Genomic DNA was extracted from macrodissected cells of paraffin-embedded primary tumor and metastatic lymph node tissues. Overexpression and somatic mutations in exons of p53 (exons 5–8) and tyrosine kinase domain of EGFR (exons 18–21) were examined by immunohistochemical staining and DNA sequencing, respectively.

Results

p53 and EGFR mutation/overexpression status were different between primary tumors and lymph node metastases in 5.4/7.2% and 28.6/33.9%, respectively. In most cases, the p53 and EGFR mutations usually preceded lymph node metastasis, and these gene statuses in the primary cancer and their lymph node metastasis were concordant (92.9 and 69.6%, respectively), which further supported the hypothesis that when these p53 mutations occur before the establishment of lymph node metastasis, they subsequently persist in the metastatic nodes. The expressions of p53 and EGFR showed 7.1 and 33.9% discordance in that order.

Conclusions

Our results reveal that p53 and EGFR mutations usually precede lymph node metastasis. The higher prevalence of EGFR heterogeneity existing in the primary tumor is not reflected in all lymph node metastasis and thus might have therapeutic implications when adjuvant therapy is considered.

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References

  1. American Joint Committee on Cancer. Lung. In: Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ, Murphy GP, editors. AJCC cancer staging manual. Philadelphia: Lippincott-Raven; 1997. p. 127–37.

  2. Fidler IJ, Hart IR. Biological diversity in metastatic neoplasms: origins and implications. Science. 1982;217:998–1003.

    Article  CAS  PubMed  Google Scholar 

  3. Weiss L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev. 2000;19:351–79.

    Article  Google Scholar 

  4. Yokota J, Kohno T. Molecular footprints of human lung cancer progression. Cancer Sci. 2004;95:197–204.

    Article  CAS  PubMed  Google Scholar 

  5. Sasatomi E, Finkelstein SD, Woods JD, Bakker A, Swalsky PA, Luketich JD, et al. Comparison of accumulated allele loss between primary tumor and lymph node metastasis in stage II non-small cell lung carcinoma: implications for the timing of lymph node metastasis and prognostic value. Cancer Res. 2002;62:2681–9.

    CAS  PubMed  Google Scholar 

  6. Sekido Y, Fong KM, Minna JD. Progress in understanding the molecular pathogenesis of human lung cancer. Biochem Biophys Acta. 1998;1378:F21–59.

    CAS  PubMed  Google Scholar 

  7. Mitsudomi T, Steinberg SM, Nau MM, Carbone D, D’Amico D, Bodner S, et al. p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene. 1992;7:171–80.

    CAS  PubMed  Google Scholar 

  8. Sozzi G, Miozzo M, Pastorino U, Pilotti S, Donghi R, Giarola M, et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 1995;55:135–40.

    CAS  PubMed  Google Scholar 

  9. Harris CC. p53 tumor suppressor gene: from the basic research laboratory to the clinic—an abridged historical perspective. Carcinogenesis. 1996;17:1187–98.

    Article  CAS  PubMed  Google Scholar 

  10. Reichel MB, Ohgaki H, Petersen I, Kleihues P. p53 mutations in primary human lung tumors and their metastases. Mol Carcinog. 1994;9:105–9.

    Article  CAS  PubMed  Google Scholar 

  11. Miller CW, Simon K, Aslo A, Kok K, Yokota J, Buys CH, et al. p53 mutations in human lung tumors. Cancer Res. 1992;52:1695–8.

    CAS  PubMed  Google Scholar 

  12. Sekido Y, Fong KM, Minna JD. Molecular genetics of lung cancer. Annu Rev Med. 2003;54;73–87.

    Article  CAS  PubMed  Google Scholar 

  13. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004;59:21–6.

    Article  CAS  PubMed  Google Scholar 

  14. Scagliotti GV, Selvaggi G, Novello S, Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res. 2004;10:4227–32s.

    Article  Google Scholar 

  15. Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspective for targeted therapies. Lung Cancer. 2003;41:s29–42.

    Article  PubMed  Google Scholar 

  16. Mendelson J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19:6550–65.

    Article  Google Scholar 

  17. Italiano A, Saint-Paul MC, Caroli-Bosc FX, François E, Bourgeon A, Benchimol D, et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications. Ann Oncol. 2005;16:1503–7.

    Article  CAS  PubMed  Google Scholar 

  18. Italiano A, Burel Vandenbos F, Otto J, Mouroux J, Fontaine D, Marcy P-Y, 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.

    Article  CAS  PubMed  Google Scholar 

  19. Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y, Kohno T, et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer. 2006;119:1491–4.

    Article  CAS  PubMed  Google Scholar 

  20. Badalian G, Barbai T, Rásó E, Derecskei K, Szendrői M, Tímár J. Phenotype of bone metastases of non-small cell lung cancer: epidermal growth factor receptor expression and K-RAS mutational status. Pathol Oncol Res. 2007;13:99–104.

    Article  CAS  PubMed  Google Scholar 

  21. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, 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.

    Article  CAS  PubMed  Google Scholar 

  22. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutation in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  CAS  PubMed  Google Scholar 

  23. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339–46.

    Article  CAS  PubMed  Google Scholar 

  24. Johnson BE, Janne PA. Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Cancer Res. 2005;65:7525–9.

    CAS  PubMed  Google Scholar 

  25. Gow CH, Chang YL, Hsu YC, Tsai MF, Wu CT, Yu CJ, et al. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor naive non-small-cell lung cancer. Ann Oncol. 2009;20:696–702.

    Article  PubMed  Google Scholar 

  26. Phelps M, Wilkins BS, Jones DB. Selective genetic analysis of p53 immunostain positive cells. Mol Pathol. 2000;53:159–61.

    Article  CAS  PubMed  Google Scholar 

  27. Chang YL, Wu CT, Lin SC, Hsiao CF, Jou YS, Lee YC. Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers. Clin Cancer Res. 2007;13:52–8.

    Article  CAS  PubMed  Google Scholar 

  28. Yatabe Y, Konishi H, Mitsudomi T, Nakamura S, Takahashi T. Topographical distributions of allelic loss in individual non-small-cell lung cancers. Am J Pathol. 2000;157:985–93.

    Article  CAS  PubMed  Google Scholar 

  29. Nakano H, Soda H, Takasu M, Tomonaga N, Yamaguchi H, Nakatomi K, et al. Heterogeneity of epidermal growth factor receptor mutations within a mixed adenocarcinoma lung nodule. Lung Cancer. 2008;60:136–40.

    Article  PubMed  Google Scholar 

  30. Park S, Holmes-Tisch AJ, Cho EY, Shim YM, Kim J, Kim HS, et al. Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in non-small cell lung cancer. J Thoracic Oncol. 2009;4:1–7.

    Article  Google Scholar 

  31. Wu SG, Shih JY. Discordant EGFR mutations between primary and metastatic tumors of non-small cell lung cancer: a review of the current literature. APJOH. 2009;1:1–8.

    Google Scholar 

  32. Yamada Y, Yoshida T, Hayashi K, Sekiya T, Yokota J, Hirohashi S, et al. P53 gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. Cancer Res. 1991;51:5800–5.

    CAS  PubMed  Google Scholar 

  33. Zhang JS, Caplin S, Bosman FT and Bebhatter J. Genetic diversity at the p53 locus between primary human colorectal adenocarcinoma and their lymph-node metastases. Int J Cancer. 1997;70:674–8.

    Article  CAS  PubMed  Google Scholar 

  34. Albanese I, Scibetta AG, Migliavacca M, Russo A, Bazan V, Tomasino RM, et al. Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations. Biochem Biophys Res Commun. 2004;325:784–91.

    Article  CAS  PubMed  Google Scholar 

  35. Takahashi K, Kohno T, Matsumoto S, Nakanishi Y, Arai Y, Yamamoto S, et al. Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells. Clin Cancer Res. 2007;13:111–20.

    Article  CAS  PubMed  Google Scholar 

  36. Yokota J. Tumor progression and metastasis. Carcinogenesis. 2000;21:497–503.

    Article  CAS  PubMed  Google Scholar 

  37. Crook T, Vousden KH. Properties of p53 mutations detected in primary and secondary cervical cancers suggests mechanisms of metastasis and involvement of environment carcinogenesis. EMBO J. 1992;11:3935–40.

    CAS  PubMed  Google Scholar 

  38. Gray JW. Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors. Cancer Cell. 2003;4:4–6.

    Article  CAS  PubMed  Google Scholar 

  39. Takahashi T, Suzuki H, Hida T, Sekido Y, Ariyoshi Y, Ueda R. The p53 gene is very frequently mutated in small-cell lung cancer with a distinct nucleotide substitution pattern. Oncogene. 1991;6:1775–8.

    CAS  PubMed  Google Scholar 

  40. Kropveld A, Van Mansfeld ADM, Nabben N, Hordijk GJ, Slootweg PJ. Discordance of p53 status in matched primary tumours and metastases in head and neck squamous cell carcinoma patients. Eur J Cancer B Oral Oncol. 1996;32B:388–93.

    Article  CAS  PubMed  Google Scholar 

  41. Oliveira LR, Ribeiro-Silva A, Zucoloto S. Prognostic significance of p53 and p63 immunolocalisation in primary and matched lymph node metastasis in oral squamous cell carcinoma. Acta Histochem. 2007;109:388–96.

    Article  PubMed  Google Scholar 

  42. Gomez-Roca C, Raynaud CM, Penault-Llorca F, Mercier O, Commo F, Morat L, et al. Differential expression of biomarkers in primary non-small cell lung cancer and metastatic sites. J Thoracic Oncol. 2009;4:1212–20.

    Article  Google Scholar 

  43. Yamauchi H, Stearns V, Hayes DF. When is a tumor marker ready for prime time? A case study of c-erb B-2 as a predictive factor in breast cancer. J Clin Oncol. 2001;9:2334–56.

    Google Scholar 

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Acknowledgment

We thank Chih-Hsin Chen for her skillful technical support and Wen-Chen Wu for his help in preparation of the manuscript and artwork. This research was sponsored by National Science Council, Republic of China, Grants NSC 96-2314-B-002-145 and NSC 97-2314-B-002-044-MY3.

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Authors and Affiliations

  1. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Yih-Leong Chang MD & Chen-Tu Wu MD

  2. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Jin-Yuan Shih MD, PhD

  3. Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Yung-Chie Lee MD, PhD

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  1. Yih-Leong Chang MD
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  2. Chen-Tu Wu MD
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  3. Jin-Yuan Shih MD, PhD
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  4. Yung-Chie Lee MD, PhD
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Correspondence to Yung-Chie Lee MD, PhD.

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Chang, YL., Wu, CT., Shih, JY. et al. Comparison of p53 and Epidermal Growth Factor Receptor Gene Status Between Primary Tumors and Lymph Node Metastases in Non-Small Cell Lung Cancers. Ann Surg Oncol 18, 543–550 (2011). https://doi.org/10.1245/s10434-010-1295-6

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