Skip to main content

Advertisement

SpringerLink
Log in

The role of human epididymis protein 4 in the diagnosis of epithelial ovarian cancer

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Epithelial ovarian cancer is one of the most lethal female genital tract cancers. Early diagnosis of EOC would benefit the patients a lot. Human epididymis protein 4 (HE4) has been regarded as a new powerful biomarker in diagnosis of EOC; we hope to obtain system knowledge of HE4 and understand the role of HE4 in diagnosis of epithelial ovarian cancer (EOC).

Methods

We searched Pubmed, Embase, Medline, and Chinese National Knowledge Infrastructure (CNKI) for articles that included HE4’s origin, characteristics, detection methods, clinical efficacy alone or combined with CA125, the risk of malignancy index, and the risk of ovarian malignancy algorithm. The diagnostic performance for the EOC and the role in the recurrence and procession in EOC were also discussed.

Results

We got 83 most related articles and found that there were significantly difference existing among the studies, such as the clinical characteristics of patients, the methodology for measuring HE4, the different cut-offs for HE4 and so on.

Conclusion

HE4 is a promising biomarker for the early diagnosis of EOC. However, each lab should establish its own reference internal of HE4.

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. Hamed EO, Ahmed H, Sedeek OB, Mohammed AM, Abd-Alla AA, Abdel GH. Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn Pathol. 2013;8:11. doi:10.1186/1746-1596-8-11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Sandri MT, Bottari F, Franchi D, Boveri S, Candiani M, Ronzoni S, et al. Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome. Gynecol Oncol. 2013;128(2):233–8. doi:10.1016/j.ygyno.2012.11.026.

    Article  CAS  PubMed  Google Scholar 

  3. Braicu EI, Fotopoulou C, Van Gorp T, Richter R, Chekerov R, Hall C, et al. Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: results from the OVCAD study. Gynecol Oncol. 2013;128(2):245–51. doi:10.1016/j.ygyno.2012.11.023.

    Article  CAS  PubMed  Google Scholar 

  4. Jacob F, Meier M, Caduff R, Goldstein D, Pochechueva T, Hacker N, et al. No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting. Gynecol Oncol. 2011;121(3):487–91. doi:10.1016/j.ygyno.2011.02.022.

    Article  CAS  PubMed  Google Scholar 

  5. Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009;112(1):40–6. doi:10.1016/j.ygyno.2008.08.031.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Park Y, Kim Y, Lee EY, Lee JH, Kim HS. Reference ranges for HE4 and CA125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer. Int J Cancer. 2012;130(5):1136–44. doi:10.1002/ijc.26129.

    Article  CAS  PubMed  Google Scholar 

  7. Yang Z, Luo Z, Zhao B, Zhang W, Zhang J, Li Z, et al. Diagnosis and preoperative predictive value of serum HE4 concentrations for optimal debulking in epithelial ovarian cancer. Oncol Lett. 2013;6(1):28–34. doi:10.3892/ol.2013.1339.

    PubMed Central  PubMed  Google Scholar 

  8. Montagnana M, Lippi G, Ruzzenente O, Bresciani V, Danese E, Scevarolli S, et al. The utility of serum human epididymis protein 4 (HE4) in patients with a pelvic mass. J Clin Lab Anal. 2009;23(5):331–5. doi:10.1002/jcla.20340.

    Article  PubMed  Google Scholar 

  9. Chan KK, Chen CA, Nam JH, Ochiai K, Wilailak S, Choon AT, et al. The use of HE4 in the prediction of ovarian cancer in Asian women with a pelvic mass. Gynecol Oncol. 2013;128(2):239–44. doi:10.1016/j.ygyno.2012.09.034.

    Article  CAS  PubMed  Google Scholar 

  10. Simmons AR, Baggerly K, Bast RJ. The emerging role of HE4 in the evaluation of epithelial ovarian and endometrial carcinomas. Oncology (Williston Park). 2013;27(6):548–56.

    PubMed Central  PubMed  Google Scholar 

  11. 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(2):350–7.

    Article  CAS  PubMed  Google Scholar 

  12. Li J, Chen H, Mariani A, Chen D, Klatt E, Podratz K, et al. HE4 (WFDC2) promotes tumor growth in endometrial cancer cell lines. Int J Mol Sci. 2013;14(3):6026–43. doi:10.3390/ijms14036026.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Galgano MT, Hampton GM, Frierson HF. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Modern Pathol. 2006;19(6):847–53.

    CAS  Google Scholar 

  14. Schummer M, Ng WV, Bumgarner RE, Nelson PS, Schummer B, Bednarski DW, et al. Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. Gene. 1999;238(2):375–85.

    Article  CAS  PubMed  Google Scholar 

  15. Hertlein L, Stieber P, Kirschenhofer A, Krocker K, Nagel D, Lenhard M, et al. Human epididymis protein 4 (HE4) in benign and malignant diseases. Clin Chem Lab Med. 2012;50(12):2181–8. doi:10.1515/cclm-2012-0097.

    Article  CAS  PubMed  Google Scholar 

  16. Jacobs IJ, Fay TN, Yovich J, Stabile I, Frost C, Turner J, et al. Serum levels of CA 125 during the first trimester of normal outcome, ectopic and anembryonic pregnancies. Hum Reprod. 1990;5(1):116–22.

    CAS  PubMed  Google Scholar 

  17. Urban N, Thorpe J, Karlan BY, McIntosh MW, Palomares MR, Daly MB, et al. Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2012;21(11):2087–94. doi:10.1158/1055-9965.EPI-12-0616.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Moore RG, Miller MC, Eklund EE, Lu KH, Bast RC Jr, Lambert-Messerlian PG. Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. Am J Obstet Gynecol. 2012;206(349):e1–7.

    Google Scholar 

  19. Lu R, Sun X, Xiao R, Zhou L, Gao X, Guo L. Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility. Biochem Biophys Res Commun. 2012;419(2):274–80. doi:10.1016/j.bbrc.2012.02.008.

    Article  CAS  PubMed  Google Scholar 

  20. Moore RG, Hill EK, Horan T, Yano N, Kim K, MacLaughlan S, et al. HE4 (WFDC2) gene overexpression promotes ovarian tumor growth. Sci Rep. 2014;4:3574. doi:10.1038/srep03574.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Gao L, Cheng HY, Dong L, Ye X, Liu YN, Chang XH, et al. The role of HE4 in ovarian cancer: inhibiting tumour cell proliferation and metastasis. J Int Med Res. 2011;39(5):1645–60.

    Article  CAS  PubMed  Google Scholar 

  22. Kong X, Chang X, Cheng H, Ma R, Ye X, Cui H. Human epididymis protein 4 inhibits proliferation of human ovarian cancer cells via the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways. Int J Gynecol Cancer. 2014;24(3):427–36. doi:10.1097/IGC.0000000000000078.

    Article  PubMed  Google Scholar 

  23. Chudecka-Glaz A, Rzepka-Gorska I, Wojciechowska I. Human epididymal protein 4 (HE4) is a novel biomarker and a promising prognostic factor in ovarian cancer patients. Eur J Gynaecol Oncol. 2012;33(4):382–90.

    CAS  PubMed  Google Scholar 

  24. Chang X, Ye X, Dong L, Cheng H, Cheng Y, Zhu L, et al. Human epididymis protein 4 (HE4) as a serum tumor biomarker in patients with ovarian carcinoma. Int J Gynecol Cancer. 2011;21(5):852–8. doi:10.1097/IGC.0b013e31821a3726.

    Article  PubMed  Google Scholar 

  25. Speeckaert MM, Speeckaert R, Delanghe JR. Human epididymis protein 4 in cancer diagnostics: a promising and reliable tumor marker. Adv Clin Chem. 2013;59:1–21.

    Article  CAS  PubMed  Google Scholar 

  26. Park Y, Lee JH, Hong DJ, Lee EY, Kim HS. Diagnostic performances of HE4 and CA125 for the detection of ovarian cancer from patients with various gynecologic and non-gynecologic diseases. Clin Biochem. 2011;44(10–11):884–8. doi:10.1016/j.clinbiochem.2011.04.011.

    Article  CAS  PubMed  Google Scholar 

  27. Li F, Tie R, Chang K, Wang F, Deng S, Lu W, et al. Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer: a meta-analysis. BMC Cancer. 2012;12:258. doi:10.1186/1471-2407-12-258.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Ferraro S, Braga F, Lanzoni M, Boracchi P, Biganzoli EM, Panteghini M. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol. 2013;66(4):273–81. doi:10.1136/jclinpath-2012-201031.

    Article  CAS  PubMed  Google Scholar 

  29. Wu L, Dai ZY, Qian YH, Shi Y, Liu FJ, Yang C. Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. Int J Gynecol Cancer. 2012;22(7):1106–12. doi:10.1097/IGC.0b013e318263efa2.

    Article  PubMed  Google Scholar 

  30. Yang Z, Wei C, Luo Z, Li L. Clinical value of serum human epididymis protein 4 assay in the diagnosis of ovarian cancer: a meta-analysis. Onco Targets Ther. 2013;6:957–66. doi:10.2147/OTT.S45681.

    PubMed Central  PubMed  Google Scholar 

  31. Lin J, Qin J, Sangvatanakul V. Human epididymis protein 4 for differential diagnosis between benign gynecologic disease and ovarian cancer: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167(1):81–5. doi:10.1016/j.ejogrb.2012.10.036.

    Article  PubMed  Google Scholar 

  32. Molina R, Escudero JM, Augé JM, Filella X, Foj L, Torné A, et al. HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol. 2011;32(6):1087–95. doi:10.1007/s13277-011-0204-3.

    Article  CAS  Google Scholar 

  33. Moore RG, Jabre-Raughley M, Brown AK, Robison KM, Miller MC, Allard WJ, et al. Comparison of a novel multiple marker assay vs the Risk of Malignancy Index for the prediction of epithelial ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol. 2010;203(3):221–8. doi:10.1016/j.ajog.2010.03.043.

    Article  Google Scholar 

  34. Nolen B, Velikokhatnaya L, Marrangoni A, De Geest K, Lomakin A, Bast RJ, et al. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol. 2010;117(3):440–5. doi:10.1016/j.ygyno.2010.02.005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Partheen K, Kristjansdottir B, Sundfeldt K. Evaluation of ovarian cancer biomarkers HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass. J Gynecol Oncol. 2011;22(4):244–52. doi:10.3802/jgo.2011.22.4.244.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Azzam AZ, Hashad DI, Kamel NA. Evaluation of HE4 as an extrabiomarker to CA125 to improve detection of ovarian carcinoma: is it time for a step forward? Arch Gynecol Obstet. 2013;288(1):167–72. doi:10.1007/s00404-013-2722-2.

    Article  CAS  PubMed  Google Scholar 

  37. Kristjansdottir B, Levan K, Partheen K, Sundfeldt K. Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer. Gynecol Oncol. 2013;131(1):52–8. doi:10.1016/j.ygyno.2013.07.094.

    Article  CAS  PubMed  Google Scholar 

  38. Braicu EI, Chekerov R, Richter R, Pop C, Nassir M, Loefgren H, et al. HE4 expression in plasma correlates with surgical outcome and overall survival in patients with first ovarian cancer relapse. Ann Surg Oncol. 2014;21(3):955–62. doi:10.1245/s10434-013-3347-1.

    Article  PubMed  Google Scholar 

  39. Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990;97(10):922–9.

    Article  CAS  PubMed  Google Scholar 

  40. Anton C, Carvalho FM, Oliveira EI, Maciel GA, Baracat EC, Carvalho JP. A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses. Clinics (Sao Paulo). 2012;67(5):437–41.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Bailey J, Tailor A, Naik R, Lopes A, Godfrey K, Hatem HM, et al. Risk of malignancy index for referral of ovarian cancer cases to a tertiary center: does it identify the correct cases? Int J Gynecol Cancer. 2006;16:30–4.

    Article  PubMed  Google Scholar 

  42. Manjunath AP, Pratapkumar, Sujatha K, Vani R. Comparison of three risk of malignancy indices in evaluation of pelvic masses. Gynecol Oncol. 2001;81(2):225–9.

    Article  CAS  PubMed  Google Scholar 

  43. Montagnana M, Danese E, Ruzzenente O, Bresciani V, Nuzzo T, Gelati M, et al. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? Clin Chem Lab Med. 2011;49(3):521–5. doi:10.1515/CCLM.2011.075.

    Article  CAS  PubMed  Google Scholar 

  44. Van Gorp T, Cadron I, Despierre E, Daemen A, Leunen K, Amant F, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer. 2011;104(5):863–70. doi:10.1038/sj.bjc.6606092.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Yuan J, Duan R, Yang H, Luo X, Xi M. Detection of serum human epididymis secretory protein 4 in patients with ovarian cancer using a label-free biosensor based on localized surface plasmon resonance. Int J Nanomed. 2012;7:2921–8.

    Article  CAS  Google Scholar 

  46. Zhou L, Xiao R, Chen Y, Zhang J, Lu RQ, Guo L. Effect of down-regulation of HE4 gene expression on biologic behavior of ovarian cancer cells. Zhonghua Bing Li Xue Za Zhi. 2013;42(10):687–90.

    CAS  PubMed  Google Scholar 

  47. Zhu YF, He LS, Zhang ZD, Huang QS. Expression of serum human epididymal secretory protein at low grade and high grade serous carcinomas. Asian Pac J Trop Med. 2012;5(12):925–30. doi:10.1016/S1995-7645(12)60175-8.

    Article  CAS  PubMed  Google Scholar 

  48. Devan SM, Pailoor J, Sthaneshwar P, Narayanan V. Pattern of tissue expression of CA-125 and HE4 in primary epithelial ovarian tumours and correlation with serum CA-125 levels. Asian Pac J Cancer Prev. 2013;14(8):4545–8.

    Article  PubMed  Google Scholar 

  49. Kurman RJ, Shih I. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34(3):433–43. doi:10.1097/PAS.0b013e3181cf3d79.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Kurman RJ, Shih I. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer-shifting the paradigm. Hum Pathol. 2011;42(7):918–31. doi:10.1016/j.humpath.2011.03.003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Yang J, Sa M, Huang M, Yang J, Xiang Z, Liu B, et al. The reference intervals for HE4, CA125 and ROMA in healthy female with electrochemiluminescence immunoassay. Clin Biochem. 2013;46(16–17):1705–8. doi:10.1016/j.clinbiochem.2013.08.019.

    Article  CAS  PubMed  Google Scholar 

  52. Bandiera E, Romani C, Specchia C, Zanotti L, Galli C, Ruggeri G, et al. Serum human epididymis protein 4 and risk for ovarian malignancy algorithm as new diagnostic and prognostic tools for epithelial ovarian cancer management. Cancer Epidemiol Biomarkers Prev. 2011;20(12):2496–506. doi:10.1158/1055-9965.EPI-11-0635.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Trudel D, Tetu B, Gregoire J, Plante M, Renaud MC, Bachvarov D, et al. Human epididymis protein 4 (HE4) and ovarian cancer prognosis. Gynecol Oncol. 2012;127(3):511–5. doi:10.1016/j.ygyno.2012.09.003.

    Article  CAS  PubMed  Google Scholar 

  54. O’Shannessy DJ, Jackson SM, Twine NC, Hoffman BE, Dezso Z, Agoulnik SI, et al. Gene expression analyses support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer. Int J Mol Sci. 2013;14(7):13687–703. doi:10.3390/ijms140713687.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Smith RA, Manassaram-Baptiste D, Brooks D, Cokkinides V, Doroshenk M, Saslow D, et al. Cancer screening in the United States, 2014: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2014;64(1):30–51. doi:10.3322/caac.21212.

    Article  PubMed  Google Scholar 

  56. Wilailak S, Chan KK, Chen C, Nam J, Ochiai K, Aw T et al. Distinguishing benign from malignant pelvic mass utilizing an algorithm with HE4, menopausal status, and ultrasound findings. J Gynecol Oncol 2015;26(1):46. doi:10.3802/jgo.2015.26.1.46.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Karlsen MA, Høgdall EVS, Christensen IJ, Borgfeldt C, Kalapotharakos G, Zdrazilova-Dubska L et al. A novel diagnostic index combining HE4, CA125 and age may improve triage of women with suspected ovarian cancer—an international multicenter study in women with an ovarian mass. Gynecol Oncol. 2015. doi:10.1016/j.ygyno.2015.06.021.

    Google Scholar 

  58. Ortiz-Munoz B, Aznar-Oroval E, Garcia GA, Covisa PA, Perez BP, Sanchez YM et al. HE4, Ca125 and ROMA algorithm for differential diagnosis between benign gynaecological diseases and ovarian cancer. Tumour Biol 2014;35(7):7249–58. doi:10.1007/s13277-014-1945-6.

    Article  Google Scholar 

  59. Chen W, Gao X, Han X, Zheng H, Guo L, Lu R. HE4 as a serum biomarker for ROMA prediction and prognosis of epithelial ovarian cancer. Asian Pac J Cancer Prev 2014;15(1):101–5. doi:10.7314/APJCP.2014.15.1.101.

    Article  PubMed  Google Scholar 

  60. Kaijser J, Van Gorp T, Smet ME, Van Holsbeke C, Sayasneh A, Epstein E et al. Are serum HE4 or ROMA scores useful to experienced examiners for improving characterization of adnexal masses after transvaginal ultrasonography? Ultrasound Obst Gyn 2014;43(1):89–97. doi:10.1002/uog.12551.

    Article  CAS  Google Scholar 

  61. Moore RG, Miller MC, Disilvestro P, Landrum LM, Gajewski W, Ball JJ et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol 2011;118(2, Part 1):280–8. doi:10.1097/AOG.0b013e318224fce2.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Kangfuqian Street 7, Zhengzhou, 450052, People’s Republic of China

    L.-T. Jia, Y.-C. Zhang, J. Li, Y. Tian & J.-F. Li

Authors
  1. L.-T. Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y.-C. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J.-F. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L.-T. Jia.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jia, LT., Zhang, YC., Li, J. et al. The role of human epididymis protein 4 in the diagnosis of epithelial ovarian cancer. Clin Transl Oncol 18, 233–239 (2016). https://doi.org/10.1007/s12094-015-1365-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-015-1365-0

Keywords

Search

Navigation