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Tumor Biology

, Volume 33, Issue 4, pp 1141–1149 | Cite as

Serum HE4 as a diagnostic and prognostic marker for lung cancer

  • Kota Iwahori
  • Hidekazu Suzuki
  • Yoshiro Kishi
  • Yoshihiro Fujii
  • Rie Uehara
  • Norio Okamoto
  • Masashi Kobayashi
  • Tomonori Hirashima
  • Ichiro Kawase
  • Tetsuji Naka
Research Article

Abstract

We evaluated the diagnostic and prognostic efficacy of human epididymis protein 4 (HE4) for lung cancer patients by using our novel enzyme-linked immunosorbent assay (ELISA) system. We measured serum HE4 levels of cancer patients including 49 lung cancer and 18 ovarian cancer patients. Furthermore, we evaluated the relationship between serum HE4 levels and overall survival after chemotherapy of 24 lung cancer patients. Serum HE4 levels were significantly higher for non-small, small cell lung cancer and ovarian cancer patients than for healthy controls. The area under the receiver operating characteristic curve (AUC) was calculated for differentiation of lung cancer patients and healthy controls. AUC for serum HE4 was 0.988 for differentiating lung cancer patients from healthy controls, with a cutoff value of 6.56 ng/ml (sensitivity = 89.8%, specificity = 100%). Serum HE4 levels were elevated in 36/40 (90.0%) non-small cell lung cancer patients, 8/9 (88.9%) small cell lung cancer patients and 8/18 (44.4%) ovarian cancer patients. High levels of serum HE4 (>15 ng/ml) after chemotherapy were significantly correlated with worse overall survival after the treatment. These findings suggest that serum HE4 is a potential diagnostic and prognostic marker for lung cancer patients.

Keywords

HE4 Tumor marker ELISA Lung cancer Chemotherapy 

Notes

Acknowledgments

We appreciate Shintaro Nomura (Nagahama Institute of Bio-Science and Technology, Shiga, Japan) for providing helpful comments on immunohistochemical analysis, Barry Ripley for outstanding editing of the manuscript and Masako Ikeda for their technical assistance. We wish to thank Y. Ito, N. Kawakami and Y. Kanazawa for their secretarial assistance. This work was supported by a grant-in-aid from the Ministry of Health, Labour and Welfare, Japan.

Conflict of interest

None.

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Fruh M. The search for improved systemic therapy of non-small cell lung cancer—what are today’s options? Lung Cancer. 2011;72:265–70.PubMedCrossRefGoogle Scholar
  3. 3.
    Martini N, Kris MG, Gralla RJ, Bains MS, McCormack PM, Kaiser LR, Burt ME, Zaman MB. The effects of preoperative chemotherapy on the resectability of non-small cell lung carcinoma with mediastinal lymph node metastases (n2 m0). Ann Thorac Surg. 1988;45:370–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Shinkai T, Saijo N, Tominaga K, Eguchi K, Shimizu E, Sasaki Y, Fujita J, Futami H, Ohkura H, Suemasu K. Serial plasma carcinoembryonic antigen measurement for monitoring patients with advanced lung cancer during chemotherapy. Cancer. 1986;57:1318–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Pujol JL, Grenier J, Daures JP, Daver A, Pujol H, Michel FB. Serum fragment of cytokeratin subunit 19 measured by cyfra 21-1 immunoradiometric assay as a marker of lung cancer. Cancer Res. 1993;53:61–6.PubMedGoogle Scholar
  6. 6.
    Miyake Y, Kodama T, Yamaguchi K. Pro-gastrin-releasing peptide(31-98) is a specific tumor marker in patients with small cell lung carcinoma. Cancer Res. 1994;54:2136–40.PubMedGoogle Scholar
  7. 7.
    Kirchhoff C, Habben I, Ivell R, Krull N. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod. 1991;45:350–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Kirchhoff C. Molecular characterization of epididymal proteins. Rev Reprod. 1998;3:86–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang K, Gan L, Jeffery E, Gayle M, Gown AM, Skelly M, Nelson PS, Ng WV, Schummer M, Hood L, Mulligan J. Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray. Gene. 1999;229:101–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Schummer M, Ng WV, Bumgarner RE, Nelson PS, Schummer B, Bednarski DW, Hassell L, Baldwin RL, Karlan BY, Hood L. Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. Gene. 1999;238:375–85.PubMedCrossRefGoogle Scholar
  11. 11.
    Hough CD, Sherman-Baust CA, Pizer ES, Montz FJ, Im DD, Rosenshein NB, Cho KR, Riggins GJ, Morin PJ. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res. 2000;60:6281–7.PubMedGoogle Scholar
  12. 12.
    Ono K, Tanaka T, Tsunoda T, Kitahara O, Kihara C, Okamoto A, Ochiai K, Takagi T, Nakamura Y. Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer Res. 2000;60:5007–11.PubMedGoogle Scholar
  13. 13.
    Welsh JB, Zarrinkar PP, Sapinoso LM, Kern SG, Behling CA, Monk BJ, Lockhart DJ, Burger RA, Hampton GM. Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2001;98:1176–81.PubMedCrossRefGoogle Scholar
  14. 14.
    Shridhar V, Lee J, Pandita A, Iturria S, Avula R, Staub J, Morrissey M, Calhoun E, Sen A, Kalli K, Keeney G, Roche P, Cliby W, Lu K, Schmandt R, Mills GB, Bast Jr RC, James CD, Couch FJ, Hartmann LC, Lillie J, Smith DI. Genetic analysis of early- versus late-stage ovarian tumors. Cancer Res. 2001;61:5895–904.PubMedGoogle Scholar
  15. 15.
    Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, Wang YC, Duran GE, Sikic TL, Caldeira S, Skomedal H, Tu IP, Hernandez-Boussard T, Johnson SW, O’Dwyer PJ, Fero MJ, Kristensen GB, Borresen-Dale AL, Hastie T, Tibshirani R, van de Rijn M, Teng NN, Longacre TA, Botstein D, Brown PO, Sikic BI. Gene expression patterns in ovarian carcinomas. Mol Biol Cell. 2003;14:4376–86.PubMedCrossRefGoogle Scholar
  16. 16.
    Lu KH, Patterson AP, Wang L, Marquez RT, Atkinson EN, Baggerly KA, Ramoth LR, Rosen DG, Liu J, Hellstrom I, Smith D, Hartmann L, Fishman D, Berchuck A, Schmandt R, Whitaker R, Gershenson DM, Mills GB, Bast Jr RC. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res. 2004;10:3291–300.PubMedCrossRefGoogle Scholar
  17. 17.
    Drapkin R, von Horsten HH, Lin Y, Mok SC, Crum CP, Welch WR, Hecht JL. Human epididymis protein 4 (he4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res. 2005;65:2162–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, Hellstrom I, Mok SC, Liu J, Bast Jr RC. Potential markers that complement expression of ca125 in epithelial ovarian cancer. Gynecol Oncol. 2005;99:267–77.PubMedCrossRefGoogle Scholar
  19. 19.
    Hellstrom I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, Drescher C, Urban N, Hellstrom KE. The he4 (wfdc2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63:3695–700.PubMedGoogle Scholar
  20. 20.
    Bingle L, Cross SS, High AS, Wallace WA, Rassl D, Yuan G, Hellstrom I, Campos MA, Bingle CD. Wfdc2 (he4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respir Res. 2006;7:61.PubMedCrossRefGoogle Scholar
  21. 21.
    Galgano MT, Hampton GM, Frierson Jr HF. Comprehensive analysis of he4 expression in normal and malignant human tissues. Mod Pathol. 2006;19:847–53.PubMedGoogle Scholar
  22. 22.
    Li J, Dowdy S, Tipton T, Podratz K, Lu WG, Xie X, Jiang SW. He4 as a biomarker for ovarian and endometrial cancer management. Expert Rev Mol Diagn. 2009;9:555–66.PubMedCrossRefGoogle Scholar
  23. 23.
    Escudero JM, Auge JM, Filella X, Torne A, Pahisa J, Molina R. Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. Clin Chem. 2011;57:1534–44.PubMedCrossRefGoogle Scholar
  24. 24.
    Steffensen KD, Waldstrom M, Brandslund I, Jakobsen A. Prognostic impact of prechemotherapy serum levels of her2, ca125, and he4 in ovarian cancer patients. Int J Gynecol Canc. 2011;21:1040–7.CrossRefGoogle Scholar
  25. 25.
    Yamashita S, Tokuishi K, Hashimoto T, Moroga T, Kamei M, Ono K, Miyawaki M, Takeno S, Chujo M, Yamamoto S, Kawahara K. Prognostic significance of he4 expression in pulmonary adenocarcinoma. Tumour Biol. 2011;32:265–71.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Kota Iwahori
    • 1
    • 2
  • Hidekazu Suzuki
    • 3
  • Yoshiro Kishi
    • 4
  • Yoshihiro Fujii
    • 4
  • Rie Uehara
    • 4
  • Norio Okamoto
    • 3
  • Masashi Kobayashi
    • 3
  • Tomonori Hirashima
    • 3
  • Ichiro Kawase
    • 3
  • Tetsuji Naka
    • 1
  1. 1.Laboratory for Immune SignalNational Institute of Biomedical InnovationIbarakiJapan
  2. 2.Department of Respiratory Medicine, Allergy, and Rheumatic DiseasesOsaka University Graduate School of MedicineSuitaJapan
  3. 3.Department of Thoracic MalignancyOsaka Prefectural Medical Center for Respiratory and Allergic DiseasesHabikinoJapan
  4. 4.Medical & Biological Laboratories, Co., Ltd.NagoyaJapan

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