Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Tissue CA125 and HE4 Gene Expression Levels Offer Superior Accuracy in Discriminating Benign from Malignant Pelvic Masses

  • Fawzy, Amal (Clinical Pathology Department, Cairo University) ;
  • Mohamed, Mohamed R (Department of Biochemistry, Faculty of Science, Ain Shams University) ;
  • Ali, Mohamed AM (Department of Biochemistry, Faculty of Science, Ain Shams University) ;
  • El-Magied, Mohamed H Abd (Clinical Pathology Department, Cairo University) ;
  • Helal, Amany M (Medical Oncology Department, National Cancer Institute, Cairo University)
  • Published : 2016.02.05
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Abstract

Background: Ovarian cancer remains a major worldwide health care issue due to the lack of satisfactory diagnostic methods for early detection of the disease. Prior studies on the role of serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in detecting ovarian cancer presented conflicting results. New tools to improve the accuracy of identifying malignancy are urgently needed. We here aimed to evaluate the diagnostic utility of tissue CA125 and HE4 gene expression in comparison to serum CA125 and HE4 in discriminating benign from malignant pelvic masses. Materials and Methods: One-hundred Egyptian women were enrolled in this study, including 60 epithelial ovarian cancer (EOC) patients and 20 benign ovarian tumor patients, as well as 20 apparently healthy women. Preoperative serum levels of CA125 and HE4 were measured by immunoassays. Tissue expression levels of genes encoding CA125 and HE4 were determined by quantitative real time polymerase chain reaction (qRT-PCR). The diagnostic performance of CA125 and HE4, measured either as mRNA or protein levels, was evaluated by receiver operating characteristic (ROC) curves. Results: The serum CA125+HE4 combination and serum HE4, with area under the curve (AUC) values of 0.935 and 0.932, respectively, performed significantly better than serum CA125 (AUC=0.592; P<0.001). Tissue CA125 and HE4 (AUC=1) performed significantly better than serum CA125 (P<0.001), serum HE4 (P=0.016) and the serum CA125+HE4 combination (P=0.018). Conclusions: Measurement of tissue CA125 and HE4 gene expression not only improves discriminatory performance, but also broadens the range of differential diagnostic possibilities in distinguishing EOC from benign ovarian tumors.

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References

  1. Bandiera E, Romani C, Specchia C, et al (2011). 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, 20, 2496-506. https://doi.org/10.1158/1055-9965.EPI-11-0635
  2. Bast RC Jr, Badgwell D, Lu Z, et al (2005). New tumor markers: CA125 and beyond. Int J Gynecol Cancer, 15, 274-81. https://doi.org/10.1111/j.1525-1438.2005.00441.x
  3. Berek JS, Crum C, Friedlander M (2012). Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet, 119, 118-29. https://doi.org/10.1111/j.1471-0528.2011.03234.x
  4. Berry NB, Cho YM, Harrington MA, et al (2004). Transcriptional targeting in ovarian cancer cells using the human epididymis protein 4 promoter. Gynecol Oncol, 92, 896-904. https://doi.org/10.1016/j.ygyno.2003.12.024
  5. Buamah P (2000). Benign conditions associated with raised serum CA-125 concentration. J Surg Oncol, 75, 264-5. https://doi.org/10.1002/1096-9098(200012)75:4<264::AID-JSO7>3.0.CO;2-Q
  6. Chung SH, Lee SY, Ju W, Kim SC (2013). Clinical efficacy of serum human epididymis protein 4 as a diagnostic biomarker of ovarian cancer: A pilot study. Obstet Gynecol Sci, 56, 234-41. https://doi.org/10.5468/ogs.2013.56.4.234
  7. DeLong ER, DeLong DM, Clarke-Pearson DeL (1988). Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics, 44, 837-45. https://doi.org/10.2307/2531595
  8. Duffy MJ, Bonfrer JM, Kulpa J, et al (2005). CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer, 15, 679 -91. https://doi.org/10.1111/j.1525-1438.2005.00130.x
  9. Escudero JM, Auge JM, Filella X, et al (2011). Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. Clin Chem, 57, 1534-44. https://doi.org/10.1373/clinchem.2010.157073
  10. Ferlay J, Soerjomataram I, Ervik M, et al (2013). GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer, Available from: http://globocan.iarc.fr, accessed on June 01, 2015.
  11. Ferraro S, Braga F, Lanzoni M, et al (2013). Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol, 66, 273-81. https://doi.org/10.1136/jclinpath-2012-201031
  12. Freydanck MK, Laubender RP, Rack B, et al (2012). Two-marker combinations for preoperative discrimination of benign and malignant ovarian masses. Anticancer Res, 32, 2003-8.
  13. Fuith LC, Daxenbichler G, Dapunt O (1987). CA 125 in the serum and tissue of patients with gynecological disease. Arch Gynecol Obstet, 241, 157-64. https://doi.org/10.1007/BF00931312
  14. Fujiwara H, Suzuki M, Takeshima N, et al (2015). Evaluation of human epididymis protein 4 (HE4) and Risk of Ovarian Malignancy Algorithm (ROMA) as diagnostic tools of type I and type II epithelial ovarian cancer in Japanese women. Tumour Biol, 36, 1045-53. https://doi.org/10.1007/s13277-014-2738-7
  15. Galgano MT, Hampton GM, Frierson HF Jr (2006). Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol, 19, 847-53. https://doi.org/10.1038/modpathol.3800612
  16. Havrilesky LJ, Whitehead CM, Rubatt JM, et al (2008). Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring for disease recurrence. Gynecol Oncol, 110, 374-82. https://doi.org/10.1016/j.ygyno.2008.04.041
  17. Hellstrom I, Raycraft J, Hayden-Ledbetter M, et al (2003). The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res, 63, 3695-700.
  18. Hertlein L, Stieber P, Kirschenhofer A, et al (2012). Human epididymis protein 4 (HE4) in benign and malignant diseases. Clin Chem Lab Med, 50, 2181-8.
  19. Holcomb K, Vucetic Z, Miller MC, Knapp RC (2011). Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women. Am J Obstet Gynecol, 205, 358. 1-6.
  20. Huhtinen K, Suvitie P, Hiissa J, et al (2009). Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer, 100, 1315-9. https://doi.org/10.1038/sj.bjc.6605011
  21. Jacob F, Meier M, Caduff R, et al (2011). No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting. Gynecol Oncol, 121, 487-91. https://doi.org/10.1016/j.ygyno.2011.02.022
  22. Karlsen MA, Sandhu N, Hogdall C, et al (2012). Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancyindex (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. Gynecol Oncol, 127, 379-83. https://doi.org/10.1016/j.ygyno.2012.07.106
  23. Kim YM, Whang DH, Park J, et al (2011). Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA125 for detecting ovarian cancer: a prospective case-control study in a Korean population. Clin Chem Lab Med, 49, 527-34.
  24. Kobayashi E, Ueda Y, Matsuzaki S, et al (2012). Biomarkers for screening, diagnosis, and monitoring of ovarian cancer. Cancer Epidemiol Biomarkers Prev, 21, 1902-12. https://doi.org/10.1158/1055-9965.EPI-12-0646
  25. Lenhard M, Stieber P, Hertlein L, et al (2011). The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses. Clin Chem Lab Med, 49, 2081-8.
  26. Li F, Tie R, Chang K, et al (2012). Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer: a meta‑analysis. BMC Cancer, 12, 258. https://doi.org/10.1186/1471-2407-12-258
  27. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods, 25, 402-8. https://doi.org/10.1006/meth.2001.1262
  28. Medeiros LR, Rosa DD, da Rosa MI, Bozzetti MC (2009). Accuracy of CA 125 in the diagnosis of ovarian tumors: a quantitative systematic review. Eur J Obstet Gynecol Reprod Biol, 142, 99-105. https://doi.org/10.1016/j.ejogrb.2008.08.011
  29. Meden H, Fattahi-Meibodi A (1998). CA 125 in benign gynecological conditions. Int J Biol Markers, 13, 231-7. https://doi.org/10.1177/172460089801300411
  30. Miralles C, Orea M, Espana P, et al (2003). Cancer antigen 125 associated with multiple benign and malignant pathologies. Ann Surg Oncol, 10, 150-4. https://doi.org/10.1245/ASO.2003.05.015
  31. Molina R, Auge JM, Escudero JM, et al (2008). Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21-1, CEA, SCC and NSE. Tumour Biol, 29, 371-80. https://doi.org/10.1159/000181180
  32. Molina R, Escudero JM, Auge JM, et al (2011). HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumour Biol, 32, 1087-95. https://doi.org/10.1007/s13277-011-0204-3
  33. Molina R, Ojeda B, Filella X, et al (1992). A prospective study of tumor markers CA 125 and CA 19.9 in patients with epithelial ovarian carcinomas. Tumour Biol, 13, 278-86. https://doi.org/10.1159/000217776
  34. Montagnana M, Danese E, Ruzzenente O, et al (2011). 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, 49, 521-5.
  35. Montagnana M, Lippi G, Ruzzenente O, et al (2009). The utility of serum human epididymis protein 4 (HE4) in patients with a pelvic mass. J Clin Lab Anal, 23, 331-5. https://doi.org/10.1002/jcla.20340
  36. Moore RG, Brown AK, Miller MC, et al (2008). The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol, 108, 402-8. https://doi.org/10.1016/j.ygyno.2007.10.017
  37. Moore RG, McMeekin DS, Brown AK, et al (2009). A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol, 112, 40-6. https://doi.org/10.1016/j.ygyno.2008.08.031
  38. Moore RG, Miller MC, Disilvestro P, et al (2011). Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol, 118, 280-8. https://doi.org/10.1097/AOG.0b013e318224fce2
  39. Moore RG, Jabre-Raughley M, Brown AK, et al (2010). 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, 203, 1-6. https://doi.org/10.1016/j.ajog.2009.12.002
  40. Niloff JM, Knapp RC, Schaetzl E, Reynolds C, Bast RC Jr (1984). CA125 antigen levels in obstetric and gynecologic patients. Obstet Gynecol, 64, 703-7.
  41. Nolen B, Velikokhatnaya L, Marrangoni A, et al (2010). Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol, 117, 440-55. https://doi.org/10.1016/j.ygyno.2010.02.005
  42. Ortiz-Munoz B, Aznar-Oroval E, Garcia Garcia A, et al (2014). HE4, Ca125 and ROMA algorithm for differential diagnosis between benign gynaecological diseases and ovarian cancer. Tumour Biol, 35, 7249-58. https://doi.org/10.1007/s13277-014-1945-6
  43. Park Y, Lee JH, Hong DJ, Lee EY, Kim HS (2011). Diagnostic performances of HE4 and CA125 for the detection of ovarian cancer from patients with various gynecologic and nongynecologic diseases. Clin Biochem, 44, 884-8. https://doi.org/10.1016/j.clinbiochem.2011.04.011
  44. Park Y, Kim Y, Lee EY, Lee JH, Kim HS (2012). Reference ranges for HE4 and CA125 in a large Asian population by automated assays anddiagnostic performances for ovarian cancer. Int J Cancer, 130, 1136-44. https://doi.org/10.1002/ijc.26129
  45. Partheen K, Kristjansdottir B, Sundfeldt K (2011). Evaluation of ovarian cancer biomarkers HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass. J Gynecol Oncol, 22, 244-52. https://doi.org/10.3802/jgo.2011.22.4.244
  46. Rosen DG, Wang L, Atkinson JN, et al (2005). Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol, 99, 267-77. https://doi.org/10.1016/j.ygyno.2005.06.040
  47. Ruggeri G, Bandiera E, Zanotti L, et al (2011). HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin Chim Acta, 412, 1447-53. https://doi.org/10.1016/j.cca.2011.04.028
  48. Seibaek L, Petersen LK, Blaakaer J, Hounsgaard L (2011). Symptom interpretation and health care seeking in ovarian cancer. BMC Women's Health, 11, 31. https://doi.org/10.1186/1472-6874-11-31
  49. Somigliana E, Vigano P, Tirelli AS, et al (2004). Use of the concomitant serum dosage of CA 125, CA 19-9 and interleukin-6 to detect the presence of endometriosis. Results from a series of reproductive age women undergoing laparoscopic surgery for benign gynecological conditions. Hum Reprod, 19, 1871-6. https://doi.org/10.1093/humrep/deh312
  50. Sturgeon CM, Duffy MJ, Stenman UH, et al (2008). National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem, 54, 11-79. https://doi.org/10.1373/clinchem.2008.105601
  51. Su Z, Graybill WS, Zhu Y (2013). Detection and monitoring of ovarian cancer. Clin Chim Acta, 415, 341-5. https://doi.org/10.1016/j.cca.2012.10.058
  52. Trape J, Filella X, Alsina-Donadeu M, et al (2011). Increased plasma concentrations of tumour markers in the absence of neoplasia. Clin Chem Lab Med, 49, 1605-20.
  53. Van Gorp T, Cadron I, Despierre E, et al (2011). HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the risk of ovarian malignancy algorithm. Br J Cancer, 104, 863-70. https://doi.org/10.1038/sj.bjc.6606092
  54. Wang J, Gao J, Yao H, et al (2014). Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol, 35, 6127-38. https://doi.org/10.1007/s13277-014-1811-6
  55. Yang Z, Wei C, Luo Z, Li L (2013). Clinical value of serum human epididymis protein 4 assay in the diagnosis of ovarian cancer: a meta-analysis. Onco Targets Ther, 6, 957-66.
  56. Yu S, Yang HJ, Xie SQ, Bao YX (2012). Diagnostic value of HE4 for ovarian cancer: a meta-analysis. Clin Chem Lab Med, 50, 1439-46.
  57. Zhen S, Bian LH, Chang LL, Gao X (2014). Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer: A meta-analysis. Mol Clin Oncol, 2, 559-66. https://doi.org/10.3892/mco.2014.279
  58. Zheng H, Gao Y (2012). Serum HE4 as a useful biomarker in discriminating ovarian cancer from benign pelvic disease. Int J Gynecol Cancer, 22, 1000-5. https://doi.org/10.1097/IGC.0b013e318249bee7

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