Ann Lab Med.  2017 Nov;37(6):526-530. 10.3343/alm.2017.37.6.526.

Clinical Usefulness of Human Epididymis Protein 4 in Lung Cancer

• Choi SI
• Jang MA
• Jeon BR
• Shin HB
• Lee YK
• Lee YW

• KMID: 2425995
• DOI: http://doi.org/10.3343/alm.2017.37.6.526

Abstract

Human epididymis protein 4 (HE4) has been suggested as a useful new biomarker of lung cancer; however, few relevant large-scale studies have been published. In this study, we evaluated the utility of serum HE4 for lung cancer detection. HE4 levels were measured in serum samples from 100 lung cancer patients, 57 patients with benign lung diseases, and 274 healthy controls by using a chemiluminescent immunoassay, and variations in HE4 levels were analyzed by clinical status such as lung cancer, benign lung disease, and healthy condition, Tumor, Lymph Nodes, Metastasis (TNM) stage, tumor score, and histological cancer type. Lung cancer patients had significantly higher serum HE4 levels than patients with benign lung diseases and healthy controls (P<0.0001). The area under the ROC curve for HE4 was 0.84 (95% confidence interval, 0.78-0.89; P<0.0001) between lung cancer patients and healthy controls. Serum HE4 levels were significantly higher in patients with advanced disease (according to TNM stage) than in healthy controls (P<0.0001). HE4 levels were significantly elevated in patients with tumors of all types, those of different histological subgroups, and those with the smallest tumors (P=0.002). This report supports the potential of serum HE4 as an ancillary diagnostic marker for lung cancer detection.

Keyword

HE4; Lung cancer; Tumor marker

MeSH Terms

Biomarkers, Tumor
Epididymal Secretory Proteins
Humans*
Immunoassay
Lung Diseases
Lung Neoplasms*
Lung*
Lymph Nodes
Male
Neoplasm Metastasis
ROC Curve

Figure

• 

  Fig. 1 Distribution of human epididymis protein 4 (HE4) levels in different groups. (A) The serum HE4 levels of 100 lung cancer patients were significantly higher than those of 57 patients with benign lung diseases and 274 healthy controls (P<0.0001). (B) Serum HE4 levels were significantly higher in TNM stage 3 and 4 patients than in healthy controls (P<0.0001). (C) HE4 levels were significantly higher in patients with all tumor scores (T1, T2, T3, and T4) than in healthy controls. (D) HE4 levels were significantly higher in patients with any histological subtype of lung cancer than in healthy controls.Abbreviation: CI, confidence interval.

Reference

1. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, editors. SEER Cancer Statistics Review, 1975-2012. Bethesda, MD: National Cancer Institute;Updated on Apr 2015. http://seer.cancer.gov/csr/1975_2012.

2. Manser R, Lethaby A, editors. Screening for lung cancer. Cochrane database of systematic reviews 2013, Issue 6. Art. No.:CD001991. John Wiley & Sons, Ltd;2013. p. 3–10. DOI: 10.1002/14651858.CD001991.pub3.

3. Tas F, Aydiner A, Topuz E, Yasasever V, Karadeniz A, Saip P. Utility of the serum tumor markers: CYFRA 21.1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCC) in squamous cell lung cancer. J Exp Clin Cancer Res. 2000; 19:477–481. PMID: 11277326.

4. Brower V. Biomarker studies abound for early detection of lung cancer. J Natl Cancer Inst. 2009; 101:11–13. PMID: 19116384.

5. Hellström I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003; 63:3695–3700. PMID: 12839961.

6. Kong SY, Han MH, Yoo HJ, Hwang JH, Lim MC, Seo SS, et al. Serum HE4 level is an independent prognostic factor in epithelial ovarian cancer. Ann Surg Oncol. 2012; 19:1707–1712. PMID: 21833668.

7. Galgano MT, Hampton GM, Frierson HF Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 2006; 19:847–853. PMID: 16607372.

8. Iwahori K, Suzuki H, Kishi Y, Fujii Y, Uehara R, Okamoto N, et al. Serum HE4 as a diagnostic and prognostic marker for lung cancer. Tumour Biol. 2012; 33:1141–1149. PMID: 22373583.

9. Sobin LH, Gospodarowicz MK, editors. TNM classification of malignant tumors. 7th ed. Oxford, UK: Wiley-Blackwell;2009.

10. Galateau-Salle F, Churg A, Roggli V, Travis WD. World Health Organization Committee for Tumors of the Pleura. The 2015 World Health Organization classification of tumors of the pleura: Advances since the 2004 classification. J Thorac Oncol. 2016; 11:142–154. PMID: 26811225.

11. Thompson RC, Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci U S A. 1986; 83:6692–6696. PMID: 3462719.

12. Wiedow O, Schröder JM, Gregory H, Young JA, Christophers E. Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J Biol Chem. 1990; 265:14791–14795. PMID: 2394696.

13. Devoogdt N, Revets H, Ghassabeh GH, De Baetselier P. Secretory leukocyte protease inhibitor in cancer development. Ann N Y Acad Sci. 2004; 1028:380–389. PMID: 15650263.

14. Zhang M, Zou Z, Maass N, Sager R. Differential expression of elafin in human normal mammary epithelial cells and carcinomas is regulated at the transcriptional level. Cancer Res. 1995; 55:2537–2541. PMID: 7780965.

15. Liu W, Yang J, Chi PD, Zheng X, Dai SQ, Chen H, et al. Evaluating the clinical significance of serum HE4 levels in lung cancer and pulmonary tuberculosis. Int J Tuberc Lung Dis. 2013; 17:1346–1353. PMID: 24025389.

16. Nagy B Jr, Krasznai ZT, Balla H, Csobán M, Antal-Szalmás P, Hernádi Z, et al. Elevated human epididymis protein 4 concentrations in chronic kidney disease. Ann Clin Biochem. 2012; 49:377–380. PMID: 22688735.

17. Tang QF, Zhou ZW, Ji HB, Pan WH, Sun MZ. Value of serum marker HE4 in pulmonary carcinoma diagnosis. Int J Clin Exp Med. 2015; 8:19014–19021. PMID: 26770527.

18. 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; 57:1534–1544. PMID: 21933899.

19. 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; 66:273–281. PMID: 23426716.