Fibulin-3 as a Diagnostic Biomarker in Patients with Malignant Mesothelioma

  • Kaya, Halide (Department of Chest Diseases, Faculty of Medicine, Dicle University) ;
  • Demir, Melike (Department of Chest Diseases, Faculty of Medicine, Dicle University) ;
  • Taylan, Mahsuk (Department of Chest Diseases, Faculty of Medicine, Dicle University) ;
  • Sezgi, Cengizhan (Department of Chest Diseases, Faculty of Medicine, Dicle University) ;
  • Tanrikulu, Abdullah Cetin (Department of Chest Diseases, Faculty of Medicine, Dicle University) ;
  • Yilmaz, Sureyya (Department of Chest Diseases, Faculty of Medicine, Dicle University) ;
  • Bayram, Mehmet (Department of Pulmonology, Faculty of Medicine, Bezmialem Vakif University) ;
  • Kaplan, Ibrahim (Department of Medical Biochemistry, Faculty of Medicine, Dicle University) ;
  • Senyigit, Abdurrahman (Department of Chest Diseases, Faculty of Medicine, Dicle University)
  • Published : 2015.03.09


Background: New tumour biomarkers are being intensely investigated for malignant mesothelioma (MM). Fibulin-3 is produced in MM but its role remains uncertain. The aim of this study was to evaluate the validity of measuring serum fibulin-3 in the diagnosis and prognosis of MM. Materials and Methods: This prospective study was performed on 43 patients and 40 healthy controls who were admitted to our hospital between January 2012 and January 2014. Data from MM patients, including demographic and clinical features, routine laboratory data, levels of serum fibulin-3, and treatment outcomes were defined as potential prognostic factors. The receiver operating characteristic (ROC) curve for fibulin-3 was used to detect the cut-off value with highest sensitivity and specificity. Univariate survival analysis was performed using the Kaplan-Meier method in patients with MM. Afterwards, the possible factors identified with univariate analyses were entered into the cox regression analysis. Results: Our results revealed that patients with MM had significantly higher serum levels of fibulin-3 than controls. The results showed that the best cut-off point was 36.6 ng/ml with an AUC (area under the curve)=0.976, sensitivity=93.0% and specificity=90.0. In our study, the initial significant poor prognostic factors were advanced stage, high white blood cell count, high platelet count, high C-reactive protein (p<0.05 for each variable). Later, according to multivariate analysis the results showed only advanced stage as significant parameter (p=0.040). Conclusions: We determined that real use for serum fibulin-3 was not for prognosis but for diagnosis in MM. Also advanced stage was associated with poor MM prognosis.


Malignant mesothelioma;serum fibulin-3;diagnosis;prognosis


  1. Agha MA, El-Habashy MM, El-Shazly RA (2014). Role of fibulin-3 in the diagnosis of malignant mesothelioma. Egyptian J Chest Diseases Tuberculosis, 63, 99-105.
  2. Antman KH (1993). Natural history and epidemiology of malignant mesothelioma. Chest, 103, 373-6.
  3. Berk S, Dogan OT, Kilickap S, et al (2013). Clinical characteristics, treatment and survival outcomes in malignant mesothelioma: Eighteen years' experience in Turkey. Asian Pac J Cancer Prev, 13, 5735-9.
  4. Boutin C, Rey F, Gouvernet J, et al (1993). Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 2: Prognosis and staging. Cancer, 72, 394-404.<394::AID-CNCR2820720214>3.0.CO;2-5
  5. Creaney J, Robinson BW (2009). Serum and pleural fluid biomarkers for mesothelioma. Curr Opin Pulm Med, 15, 366-70.
  6. Creaney J, Dick IM, Meniawy TM, et al (2014). Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma. Thorax, 69, 895-902.
  7. Edwards JG, Abrams KR, Leverment JN, et al (2000). Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax, 55, 731-5.
  8. Hefler LA, Concin N, Hofstetter G, et al (2008). Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer. Clin Cancer Res, 14, 710-4.
  9. Hollevoet K, Reitsma JB, Creaney J, et al (2012). Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol, 30, 1541-9.
  10. Hu B, Thirtamara-Rajamani KK, Sim H, Viapiano MS (2009). Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion. Mol Cancer Res, 7, 1756-70.
  11. Kim EJ, Lee SY, Woo MK, et al (2012). Fibulin-3 promoter methylation alters the invasive behavior of non-small cell lung cancer cell lines via MMP-7 and MMP-2 regulation. Int J Oncol, 40, 402-8.
  12. Kim YJ, Yoon HY, Kim SK, et al (2011). EFEMP1 as a novel DNA methylation marker for prostate cancer: array-based DNA methylation and expression profiling. Clin Cancer Res, 17, 4523-30.
  13. Komurcuoglu B, Cirak AK, Kirakli SC, et al (2014). Prognostic factors affecting survival in malignant pleural mesothelioma: analysis of 125 subjects. Tumori, 100, 55-9.
  14. Metintas M, Metintas S, Ucgun I, et al (2001). Prognostic factors in diffuse malignant pleural mesothelioma: pretreatment clinical and laboratory characteristics. Respir Med, 95, 829-35.
  15. Metintas M, Metintas S, Ak G, et al (2008). Epidemiology of pleural mesothelioma in a population with non-occupational asbestos exposure. Respirology, 13, 117-21.
  16. Metintas S, Metintas M, Ucgun I, Oner U (2002). Malignant mesothelioma due to environmental exposure to asbestos: follow-up of a Turkish cohort living in a rural area. Chest, 122, 2224-9.
  17. Nojiri S, Gemba K, Aoe K, et al (2011). Survival and Prognostic Factors in Malignant Pleural Mesothelioma: A Retrospective Study of 314 patients in the West Part of Japan. Jpn J Clin Oncol, 41, 32-9.
  18. Nomoto S, Kanda M, Okamura Y, et al (2010). Epidermal growth factor-containing fibulin-like extracellular matrix protein 1, EFEMP1, a novel tumor-suppressor gene detected in hepatocellular carcinoma using double combination array analysis. Ann Surg Oncol, 17, 923-32.
  19. O'Dowd C, McRae LA, McMillan DC, Kirk A, Milroy R (2010). Elevated preoperative C- reactive protein predicts poor cancer specific survival in patients undergoing resection for non-small cell lung cancer. J Thorac Oncol, 5, 988-92.
  20. Ordonez NG (2003). The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol, 27, 1031-51.
  21. Pass HI, Levin SM, Harbut MR, et al (2012). Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med, 367, 1417-27.
  22. Pierce BL, Ballard-Barbash R, Bernstein L, et al (2009). Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol, 27, 3437-44.
  23. Rusch VW, Venkatraman ES (1999). Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg, 68, 1799-804.
  24. Senyigit A, Babayigit C, Gokirmak M, et al (2000). Incidence of malignant pleural mesothelioma due to environmental asbestos fiber exposure in the southeast of Turkey. Respiration, 67, 610-4.
  25. Tanrikulu AC, Abakay A, Kaplan MA, et al (2010). A clinical, radiographic and laboratory evaluation of prognostic factors in 363 patients with malignant pleural mesothelioma. Respiration, 80, 480-7.
  26. Teta MJ, Mink PJ, Lau E, Sceurman BK, Foster ED (2008). US mesothelioma patterns 1973-2002: indicators of change and insights into background rates. Eur J Cancer Prev, 17, 525-34.
  27. Tong JD, Jiao NL, Wang YX, Zhang YW, Han F (2011). Downregulation of fibulin-3 gene by promoter methylation in colorectal cancer predicts adverse prognosis. Neoplasma, 58, 441-8.
  28. Van Gelder T, Damhuis RAM, Hoogsteden HC (1994). Prognostic factors and survival in malignant pleural mesothelioma. Eur Respir J, 7, 1035-38.
  29. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al (2003). Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol, 21, 2636-44.
  30. Wang CS, Sun CF (2009). C-reactive protein and malignancy: clinico-pathological association and therapeutic implication. Chang Gung Med J, 32, 471-82.
  31. Zhang Y, Marmorstein LY (2010). Focus on molecules: fibulin-3 (EFEMP1). Exp Eye Res, 90, 374-5.

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