Annals of Surgical Oncology

, Volume 23, Supplement 5, pp 746–754 | Cite as

CD151 Gene and Protein Expression Provides Independent Prognostic Information for Patients with Adenocarcinoma of the Esophagus and Gastroesophageal Junction Treated by Esophagectomy

  • Oliver M. Fisher
  • Angelique J. Levert-Mignon
  • Christopher W. Lehane
  • Natalia K. Botelho
  • Jesper L. V. Maag
  • Melissa L. Thomas
  • Melanie Edwards
  • Sarah J. Lord
  • Yuri V. Bobryshev
  • David C. Whiteman
  • Reginald V. LordEmail author
Gastrointestinal Oncology



Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient’s tumor biology and prognosis.


Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx)-naïve patients with external validation in a separate cohort of 62 CRTx-naïve patients and 169 patients with advanced-stage disease treated with CRTx.


As a novel prognostic biomarker after external validation, CD151 showed promise. Patients exhibiting high levels of CD151 (≥median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9 months; p = 0.01). This effect persisted in a multivariable Cox-regression model with adjustment for tumor stage [adjusted hazard ratio (aHR), 0.33; 95 % confidence interval (CI), 0.14–0.78; p = 0.01] and was further corroborated through immunohistochemical analysis (aHR, 0.22; 95 % CI, 0.08–0.59; p = 0.003). This effect was not found in the separate cohort of CRTx-exposed patients.


Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.


Gene Expression Omnibus Validation Cohort Multimodality Therapy Resection Margin Status CD151 Protein Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Oliver M. Fisher is supported by the Australian National Health & Medical Research Council (NHMRC; GNT1094423) and the Swiss National Science Foundation (P1SKP3_161806). David C. Whiteman is supported by a Research Fellowship (APP1058522) from the NHMRC. The Australian Cancer Study was supported by NHMRC Program Grants (#552429). PROBENET was supported by an NHMRC Centre of Research Excellence Grant (APP1040947) and this study was supported in part by Darryl and Ann Courtney O’Connor through the Curran Foundation of St. Vincent’s Hospital.


None to declare.

Supplementary material

10434_2016_5504_MOESM1_ESM.docx (34.9 mb)
Supplementary material 1 (DOCX 35730 kb)


  1. 1.
    Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology. 1993;104:510–3.PubMedGoogle Scholar
  2. 2.
    Blot WJ, Devesa SS, Fraumeni JF Jr. Continuing climb in rates of esophageal adenocarcinoma: an update. JAMA. 1993;270:1320.CrossRefPubMedGoogle Scholar
  3. 3.
    Bytzer P, Christensen PB, Damkier P, Vinding K, Seersholm N. Adenocarcinoma of the esophagus and Barrett’s esophagus: a population-based study. Am J Gastroenterol. 1999;94:86–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Eheman C, Henley SJ, Ballard-Barbash R, et al. Annual report to the nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. 2012;118:2338–66.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52.CrossRefPubMedGoogle Scholar
  7. 7.
    Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371:2499–509.CrossRefPubMedGoogle Scholar
  8. 8.
    van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Rice TW, Blackstone EH, Rybicki LA, et al. Refining esophageal cancer staging. J Thorac Cardiovasc Surg. 2003;125:1103–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Peters CJ, Rees JR, Hardwick RH, et al. A 4-gene signature predicts survival of patients with resected adenocarcinoma of the esophagus, junction, and gastric cardia. Gastroenterology. 2010;139:1995–2004 e15.Google Scholar
  11. 11.
    Weaver JM, Ross-Innes CS, Fitzgerald RC. The ‘-omics’ revolution and oesophageal adenocarcinoma. Nat Rev Gastroenterol Hepatol. 2014;11:19–27.CrossRefPubMedGoogle Scholar
  12. 12.
    Peters CJ, Hardwick RH, Vowler SL, Fitzgerald RC, Oesophageal Cancer C, Molecular Stratification Study G. Generation and validation of a revised classification for oesophageal and junctional adenocarcinoma. Br J Surg. 2009;96:724–33.CrossRefPubMedGoogle Scholar
  13. 13.
    Korst RJ, Rusch VW, Venkatraman E, et al. Proposed revision of the staging classification for esophageal cancer. J Thorac Cardiovasc Surg. 1998;115:660–69;discussion 9–70.CrossRefPubMedGoogle Scholar
  14. 14.
    Pedrazzani C, deManzoni G, Marrelli D, et al. Nodal staging in adenocarcinoma of the gastroesophageal junction: proposal of a specific staging system. Ann Surg Oncol. 2007;14:299–305.CrossRefPubMedGoogle Scholar
  15. 15.
    Rice TW, Ishwaran H, Hofstetter WL, et al. Esophageal cancer: associations with (pN+) lymph node metastases. Ann Surg. 2016. doi: 10.1097/SLA.0000000000001594.Google Scholar
  16. 16.
    Ong CA, Shapiro J, Nason KS, et al. Three-gene immunohistochemical panel adds to clinical staging algorithms to predict prognosis for patients with esophageal adenocarcinoma. J Clin Oncol. 2013;31:1576–82.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Whiteman DC, Sadeghi S, Pandeya N, et al. Combined effects of obesity, acid reflux, and smoking on the risk of adenocarcinomas of the oesophagus. Gut. 2008;57:173–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Fisher OM, Levert-Mignon AJ, Lord SJ, et al. Cathepsin E is a novel highly overexpressed biomarker in Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology. 2014;146(Suppl 1):S-1–S-1099.Google Scholar
  19. 19.
    Stanley KK, Szewczuk E. Multiplexed tandem PCR: gene profiling from small amounts of RNA using SYBR Green detection. Nucleic Acids Res. 2005;33:e180.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Botelho NK, Schneiders FI, Lord SJ, et al. Gene expression alterations in formalin-fixed, paraffin-embedded Barrett esophagus and esophageal adenocarcinoma tissues. Cancer Biol Ther. 2010;10:172–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Bobryshev YV, Freeman AK, Botelho NK, Tran D, Levert-Mignon AJ, Lord RV. Expression of the putative stem cell marker Musashi-1 in Barrett’s esophagus and esophageal adenocarcinoma. Dis Esophagus. 2010;23:580–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Buskens CJ, Van Rees BP, Sivula A, et al. Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology. 2002;122:1800–7.CrossRefPubMedGoogle Scholar
  23. 23.
    R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna; 2013.Google Scholar
  24. 24.
    Hemler ME. Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer. 2014;14:49–60.CrossRefPubMedGoogle Scholar
  25. 25.
    Sadej R, Grudowska A, Turczyk L, Kordek R, Romanska HM. CD151 in cancer progression and metastasis: a complex scenario. Lab Invest. 2014;94:41–51.CrossRefPubMedGoogle Scholar
  26. 26.
    Ang J, Lijovic M, Ashman LK, Kan K, Frauman AG. CD151 protein expression predicts the clinical outcome of low-grade primary prostate cancer better than histologic grading: a new prognostic indicator? Cancer Epidemiol Biomarkers Prev. 2004;13(11 Pt 1):1717–21.PubMedGoogle Scholar
  27. 27.
    Tokuhara T, Hasegawa H, Hattori N, et al. Clinical significance of CD151 gene expression in non-small cell lung cancer. Clin Cancer Res. 2001;7:4109–14.PubMedGoogle Scholar
  28. 28.
    Suzuki S, Miyazaki T, Tanaka N, et al. Prognostic significance of CD151 expression in esophageal squamous cell carcinoma with aggressive cell proliferation and invasiveness. Ann Surg Oncol. 2011;18:888–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Novitskaya V, Romanska H, Dawoud M, Jones JL, Berditchevski F. Tetraspanin CD151 regulates growth of mammary epithelial cells in three-dimensional extracellular matrix: implication for mammary ductal carcinoma in situ. Cancer Res. 2010;70:4698–708.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sadej R, Romanska H, Kavanagh D, et al. Tetraspanin CD151 regulates transforming growth factor beta signaling: implication in tumor metastasis. Cancer Res. 2010;70:6059–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Chien CW, Lin SC, Lai YY, et al. Regulation of CD151 by hypoxia controls cell adhesion and metastasis in colorectal cancer. Clin Cancer Res. 2008;14:8043–51.CrossRefPubMedGoogle Scholar
  32. 32.
    Minner S, De Silva C, Rink M, et al. Reduced CD151 expression is related to advanced tumour stage in urothelial bladder cancer. Pathology. 2012;44:448–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Voss MA, Gordon N, Maloney S, et al. Tetraspanin CD151 is a novel prognostic marker in poor outcome endometrial cancer. Br J Cancer. 2011;104:1611–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Smithers BM, Fahey PP, Corish T, et al. Symptoms, investigations, and management of patients with cancer of the oesophagus and gastro-oesophageal junction in Australia. Med J Aust. 2010;193:572–7.PubMedGoogle Scholar
  35. 35.
    Talsma K, van Hagen P, Grotenhuis BA, et al. Comparison of the 6th and 7th editions of the UICC-AJCC TNM classification for esophageal cancer. Ann Surg Oncol. 2012;19:2142–8.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zevian S, Winterwood NE, Stipp CS. Structure-function analysis of tetraspanin CD151 reveals distinct requirements for tumor cell behaviors mediated by alpha3beta1 versus alpha6beta4 integrin. J Biol Chem. 2011;286:7496–506.CrossRefPubMedGoogle Scholar
  37. 37.
    Yang XH, Flores LM, Li Q, et al. Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists. Cancer Res. 2010;70:2256–63.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • Oliver M. Fisher
    • 1
    • 2
    • 6
  • Angelique J. Levert-Mignon
    • 1
  • Christopher W. Lehane
    • 1
  • Natalia K. Botelho
    • 1
  • Jesper L. V. Maag
    • 2
    • 3
  • Melissa L. Thomas
    • 1
  • Melanie Edwards
    • 4
  • Sarah J. Lord
    • 1
    • 5
    • 6
  • Yuri V. Bobryshev
    • 1
  • David C. Whiteman
    • 7
  • Reginald V. Lord
    • 1
    • 6
    Email author
  1. 1.Gastroesophageal Cancer ProgramSt. Vincent’s Centre for Applied Medical ResearchSydneyAustralia
  2. 2.School of Medical SciencesUNSW AustraliaSydneyAustralia
  3. 3.Genomics & Epigenetics DivisionGarvan Institute of Medical ResearchSydneyAustralia
  4. 4.Douglass Hanley Moir PathologySydneyAustralia
  5. 5.NHMRC Clinical Trials CentreUniversity of SydneySydneyAustralia
  6. 6.Department of Surgery, School of MedicineUniversity of Notre DameSydneyAustralia
  7. 7.QIMR Berghofer Medical Research InstituteBrisbaneAustralia

Personalised recommendations