Skip to main content

Advertisement

SpringerLink
Log in

Polymorphism in Epidermal Growth Factor Receptor Intron 1 Predicts Prognosis of Patients with Esophageal Cancer after Chemoradiation and Surgery

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The EGFR gene has been demonstrated to be an important factor influencing treatment response for various cancers, and its expression has been shown to be modified by the polymorphic CA repeat length at the 5′-regulatory sequence in intron 1. We investigated whether this EGFR polymorphism is associated with prognosis in patients with esophageal cancer after concurrent chemoradiotherapy (CCRT) and esophagectomy.

Methods

A cohort of 148 patients with esophageal cancer received cisplatin-based CCRT (concurrently combined with 40 Gy irradiation) and subsequent esophagectomy. Their EGFR genotypes were determined by polymerase chain reaction from leukocyte DNA, which was obtained before treatment and was correlated with patient survival.

Results

Patients with the homozygous short allele (<20 CA) of the EGFR gene in intron 1 were more likely to have a shorter duration of survival after CCRT and surgery than those with the homozygous long allele [adjusted hazard ratio (HR) (95% confidence interval [CI]) of death: 1.88 (1.02–3.49); P = 0.045]. This unfavorable prognostic effect of EGFR homozygous short CA repeat was mainly manifested in patients with good response to CCRT [adjusted HR (95% CI) of death 3.40 (1.06–10.89); P = 0.039]; it was less evident in those with poor response to CCRT [adjusted HR (95% CI) 1.40 (0.65–3.02); P = 0.384].

Conclusions

The EGFR CA repeat genetic polymorphism may act as a valuable molecular predictor of clinical outcome of esophageal cancer after CCRT and esophagectomy, especially in those with good response to CCRT.

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
Fig. 2

Similar content being viewed by others

References

  1. McKinney A, Sharp L, Macfarlane GJ, Muir CS. Oesophageal and gastric cancer in Scotland, 1960–90. Br J Cancer. 1995;71:411–5.

    Article  PubMed  CAS  Google Scholar 

  2. Moller H. Incidence of cancer of oesophagus, cardia and stomach in Denmark. Eur J Cancer Prev. 1992;1:159–64.

    Article  PubMed  CAS  Google Scholar 

  3. Moyana TN, Janoski M. Recent trends in the epidemiology of esophageal cancer. Comparison of epidermoid- and adenocarcinomas. Ann Clin Lab Sci. 1996;26:480–6.

    PubMed  CAS  Google Scholar 

  4. Ilson DH, Kelsen DP. Combined modality therapy in the treatment of esophageal cancer. Semin Oncol. 1994;21:493–507.

    PubMed  CAS  Google Scholar 

  5. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–7.

    Article  PubMed  CAS  Google Scholar 

  6. Swisher SG, Holmes EC, Hunt KK, Doty JE, Zinner MJ, McFadden DW. The role of neoadjuvant therapy in surgically resectable esophageal cancer. Arch Surg. 1996;131:819–24.

    PubMed  CAS  Google Scholar 

  7. De Vita F, Di Martino N, Orditura M, Cosenza A, Galizia G, Del Genio A, et al. Preoperative chemoradiotherapy for squamous cell carcinoma and adenocarcinoma of the esophagus: a phase II study. Chest. 2002;122:1302–8.

    Article  PubMed  Google Scholar 

  8. Hofstetter W, Swisher SG, Correa AM, Hess K, Putnam JB Jr, Ajani JA, et al. Treatment outcomes of resected esophageal cancer. Ann Surg. 2002;236:376–84.

    Article  PubMed  Google Scholar 

  9. Gibault L, Metges JP, Conan-Charlet V, Lozac’h P, Robaszkiewicz M, Bessaguet C, et al. Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer. Br J Cancer. 2005;93:107–15.

    Article  PubMed  CAS  Google Scholar 

  10. Gotoh M, Takiuchi H, Kawabe S, Ohta S, Kii T, Kuwakado S, et al. Epidermal growth factor receptor is a possible predictor of sensitivity to chemoradiotherapy in the primary lesion of esophageal squamous cell carcinoma. Jpn J Clin Oncol. 2007;37:652–7.

    Article  PubMed  Google Scholar 

  11. Gebhardt F, Zanker KS, Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem. 1999;274:13176–80.

    Article  PubMed  CAS  Google Scholar 

  12. Buerger H, Gebhardt F, Schmidt H, Beckmann A, Hutmacher K, Simon R, et al. Length and loss of heterozygosity of an intron 1 polymorphic sequence of EGFR is related to cytogenetic alterations and epithelial growth factor receptor expression. Cancer Res. 2000;60:854–7.

    PubMed  CAS  Google Scholar 

  13. Amador ML, Oppenheimer D, Perea S, Maitra A, Cusatis G, Iacobuzio-Donahue C, et al. An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res. 2004;64:9139–43.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang W, Park DJ, Lu B, Yang DY, Gordon M, Groshen S, et al. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res. 2005;11:600–5.

    PubMed  CAS  Google Scholar 

  15. Greene FL, Page DL, Fleming ID. editors. Esophagus. In: American Joint Committee on Cancer (AJCC) cancer staging manual. 6th ed. New York: Springer; 2002. p. 167–78.

  16. Wu MT, Lee YC, Chen CJ, Yang PW, Lee CJ, Wu DC, et al. Risk of betel chewing for oesophageal cancer in Taiwan. Br J Cancer. 2001;85:658–60.

    Article  PubMed  CAS  Google Scholar 

  17. Schneider PM, Baldus SE, Metzger R, Kocher M, Bongartz R, Bollschweiler E, et al. Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification. Ann Surg. 2005;242:684–92.

    Article  PubMed  Google Scholar 

  18. Wu TT, Chirieac LR, Abraham SC, Krasinskas AM, Wang H, Rashid A, et al. Excellent interobserver agreement on grading the extent of residual carcinoma after preoperative chemoradiation in esophageal and esophagogastric junction carcinoma: a reliable predictor for patient outcome. Am J Surg Pathol. 2007;31:58–64.

    Article  PubMed  Google Scholar 

  19. Zhang W, Stoehlmacher J, Park DJ, Yang D, Borchard E, Gil J, et al. Gene polymorphisms of epidermal growth factor receptor and its downstream effector, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2005;5:124–31.

    Article  PubMed  Google Scholar 

  20. Wei Q, Chen L, Sheng L, Nordgren H, Wester K, Carlsson J. EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases. Int J Oncol. 2007;31:493–9.

    PubMed  Google Scholar 

  21. Carpenter G, Cohen S. Epidermal growth factor. Annu Rev Biochem. 1979;48:193–216.

    Article  PubMed  CAS  Google Scholar 

  22. Liang K, Ang KK, Milas L, Hunter N, Fan Z. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys. 2003;57:246–54.

    Article  PubMed  CAS  Google Scholar 

  23. Milas L, Fan Z, Andratschke NH, Ang KK. Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys. 2004;58:966–71.

    Article  PubMed  CAS  Google Scholar 

  24. Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–6.

    PubMed  CAS  Google Scholar 

  25. Chen X, Yeung TK, Wang Z. Enhanced drug resistance in cells coexpressing ErbB2 with EGF receptor or ErbB3. Biochem Biophys Res Commun. 2000;277:757–63.

    Article  PubMed  CAS  Google Scholar 

  26. Jain M, Kumar S, Upadhyay R, Lal P, Tiwari A, Ghoshal UC, et al. Influence of apoptosis (BCL2, FAS), cell cycle (CCND1) and growth factor (EGF, EGFR) genetic polymorphisms on survival outcome: an exploratory study in squamous cell esophageal cancer. Cancer Biol Ther. 2007;6:1553–8.

    Article  PubMed  CAS  Google Scholar 

  27. Dubey S, Stephenson P, Levy DE, Miller JA, Keller SM, Schiller JH, et al. EGFR dinucleotide repeat polymorphism as a prognostic indicator in non–small cell lung cancer. J Thorac Oncol. 2006;1:406–12.

    Article  PubMed  Google Scholar 

  28. Mariette C, Piessen G, Briez N, Triboulet JP. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg. 2008;247:365–71.

    Article  PubMed  Google Scholar 

  29. Bandyopadhyay D, Mandal M, Adam L, Mendelsohn J, Kumar R. Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells. J Biol Chem. 1998;273:1568–73.

    Article  PubMed  CAS  Google Scholar 

  30. Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Raju U, Milas L, et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem. 2005;280:31182–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by the National Science Council (NSC98-2314-B002-076-MY2; NSC99-2627-B002-002), and National Health Research Institutes (NHRI-EX100-10032BI) of the Republic of China. We thank the staff of the Second Core Lab, Department of Medical Research, National Taiwan University Hospital, for technical support.

Author information

Authors and Affiliations

  1. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Jang-Ming Lee MD, PhD, Pei-Wen Yang PhD, Ying-Hao Wang MS, Tzu-Hsuen Chuang MS, Jin-Shing Chen MD, PhD, Hsao-Hsun Hsu MD, Pei-Ming Huang MD, Shuenn-Wen Kuo MD & Yung-Chie Lee MD, PhD

  2. Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan

    Shi-Yi Yang BS

  3. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Chia-Tung Shun MD

  4. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Chih-Hung Hsu MD, PhD, Chia-Chi Lin MD, PhD & Jason Chia-Hsien Cheng MD, PhD

  5. Department of Family Medicine, Graduate Institute of Occupational Safety and Health, Kaohsiung, Taiwan

    Ming-Tsang Wu MD, ScD

Authors
  1. Jang-Ming Lee MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shi-Yi Yang BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pei-Wen Yang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chia-Tung Shun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming-Tsang Wu MD, ScD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chih-Hung Hsu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chia-Chi Lin MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jason Chia-Hsien Cheng MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying-Hao Wang MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tzu-Hsuen Chuang MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jin-Shing Chen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hsao-Hsun Hsu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pei-Ming Huang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shuenn-Wen Kuo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yung-Chie Lee MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jang-Ming Lee MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, JM., Yang, SY., Yang, PW. et al. Polymorphism in Epidermal Growth Factor Receptor Intron 1 Predicts Prognosis of Patients with Esophageal Cancer after Chemoradiation and Surgery. Ann Surg Oncol 18, 2066–2073 (2011). https://doi.org/10.1245/s10434-011-1559-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-1559-9

Keywords

Search

Navigation