Methylation Status and Immunohistochemistry of BRCA1 in Epithelial Ovarian Cancer

  • Pradjatmo, Heru (Department of Obstetric and Gynecology, Faculty of Medicine, Universitas Gadjah Mada) ;
  • Dasuki, Djaswadi (Department of Obstetric and Gynecology, Faculty of Medicine, Universitas Gadjah Mada) ;
  • Anwar, Mohammad (Department of Obstetric and Gynecology, Faculty of Medicine, Universitas Gadjah Mada) ;
  • Mubarika, Sofia (Department of Histology and Biomolecular, Faculty of Medicine, Universitas Gadjah Mada) ;
  • Harijadi, Harijadi (Department of Pathology, Faculty of Medicine, Universitas Gadjah Mada)
  • Published : 2014.11.28


Background: Cancer initiation and progression are controlled by genetic and epigenetic events. One epigenetic process which is widely known is DNA methylation, a cause of gene silencing. If a gene is silenced the protein which it encodes will not expressed. Objectives: 1. Identify the methylation status of BRCA1 in patients with epithelial ovarian cancer (EOC)and assess BRCA1 protein expression in tumor tissue. 2. Examine whether BRCA1 gene methylation and BRCA1 protein are associated with survival of epithelial ovarian cancer patients. Methods: The study design was a prospective-cohort study, conducted at Sardjito hospital, Yogyakarta, Indonesia. Results: A total of 69 cases were analyzed in this study. The data showed that the methylation status of BRCA1 in EOC was positive in 89.9%, with clear protein expression of BRCA1 in 31.9%. Methylation status and expression of BRCA1 were not prognosticators of EOC patients. Menarche, CA125 level, clinical stage and residual tumor were independent factors for prognosis.


  1. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Monntz FJl (2002). Suvival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol, 20, 1248-59.
  2. Chan JK, Urban R, Cheung MK, et al (2006). Ovarian cancer in younger vs older women: a population-based analysis. Br J Cancer, 95, 1314-20.
  3. Chiang JW, Karlan BY, Cass I, Baldwin RL (2006). BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecol Oncol, 101, 403-10.
  4. Duska LR, Chang YC, Flynn CE, et al (1999). Epithelial ovarian carcinoma in the reproductive age group. Cancer, 85, 2623-9.<2623::AID-CNCR19>3.0.CO;2-O
  5. Elstrand MB, Sandstad B, Oksefjell H, Davidson B, Trope CG (2012). Prognostic significance of residual tumor in patients with epithelial ovarian carcinoma stage IV in a 20 years perspective. Acta Obstet Gynecol Scan, 91, 308-17.
  6. Esteller M, Corn PG, Baylin, SB (2001). Herman JG. A gene hypermethylation profile of human cancer. Cancer Res, 61, 3225-9.
  7. Esteller M, Sanchez-Cespedes M, Rosell R, et al (1999). Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res, 59, 67-70.
  8. Hahn WC, Weinberg RA (2002). Rules for making human tumor cells. N Engl J Med, 347, 1593-603.
  9. Heo I, Joo C, Cho J (2008). Lin28 mediate terminal undylation of let-7 precursur microRNA. Mol Cell, 32, 276-8.
  10. Hilton JL, Geisler JP, Rathe JA, et al (2002). Inactivation of BRCA1 and BRCA2 in Ovarian Cancer. J Natl Cancer Inst, 94, 1396-406.
  11. Hoffman BL, Schorge JO, Schaffer JL, et al (2012). Epithelial Ovarian Cancer. In Williams Gynecology, 2nd Ed, Mc Graw Hill Co, 853-78.
  12. Bai X, Fu, Y, Xue, H, et al (2014). BRCA1 promoter methylation in sporadic epithelal ovarian carsinoma: Association with low expression of BRCA1, improved survival and coexpression of DNA methyltransferases. Oncol Letters, 7, 1088-96.
  13. Bast Jr RC, Ravdin P, Hayes DF, et al (2000). Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American society of clinical oncology. J Clin Oncol, 19, 1865-78.
  14. Hogdall EV, Christensen L, Kjaer SK, et al (2007). CA 125 expression pattern, prognosis and correlation with serum CA 125 in ovarian tumor patients from the Danish "Malova" ovarian cancer study. Gynecol Oncol, 104, 508-17.
  15. Issa J-P J, Kantarjian HM, Kirkpatrick P (2005). Fresh from the pipeline azacitidine. Nat Rev, 4, 275-6.
  16. Jacobs I, Bast RC (1989). The CA125 tumour-associated antigen: a review of the literature. Human Reprod, 4, 1-12.
  17. Kawahara N, Nishikura K (2009). Regulation of the miRNA function by RNA editing. Tanpakushitsu Kakusan Koso, 54, 1133-40.
  18. Laird PW (2003). The power and the promise of DNA methylation markers. Nat Rev Cancer, 3, 253-66.
  19. Lan VTT, Thuan TB, Thu DM, et al (2013). Methylation profile of BRCA1, RASSF1A and ER in Vietnamese women with Ovarian Cancer. Asian Pac J Cancer Prev, 14, 7713-8.
  20. Massi D, Susini T, Savino L, et al (1996). Epithelial ovarian tumors in the reproductive age group: age is not an independent prognostic factor. Cancer, 77, 1131-36..<1131::AID-CNCR19>3.0.CO;2-2
  21. Landis SH, Murray T, Bolden S, Wingo P (1998). Cancer statistics. CA Cancer J Clin, 48, 6-30.
  22. Lesnock JL, Darcy KM, Tian C, et al (2013). BRCA1 expression and improved survival in ovarian cancer patients treated with intaperitoneal cisplatin and paclitaxel: a gynecologic oncology group study. Br J Cancer, 108, 1231-37.
  23. Li C, Feng Y, Coukos G, Zhang L (2011). MicroRNAs in epithelial ovarian cancer. In William CS Cho Editor. in MicroRNAs in Cancer Translational Research. Springer Science, 309-42
  24. Montavon C, Gloss BS, Warton K, et al (2012). Prognostic and diagnostic significance of DNA methylation patterns in high grade serous ovarian cancer. Gynecol Oncol, 124, 582-88.
  25. Munkarah AR, Hallum AV, Morris M, et al (1997). Prognostic significance of residual disease in patients with stage IV epithelial ovarian cancer. Gynecol Oncol, 64, 13-7.
  26. Nagele F, Petru E, Medl M, et al (1995). Preoperative CA 125: an independent prognostic factor in patients with stage I epithelial ovarian cancer. Obstet Gynecol, 86, 259-64.
  27. Paramasivam S, Tripcony L, Crandon A, et al (2005). Prognostic importance of preoperative CA-125 in international federation of gynecology and obstetrics stage I epithelial ovarian ancer: an Australian multicenter study. J Clin Oncol, 23, 1-5.
  28. Petri AL, Hogdall EV, Christensen IBJ, et al (2006). Preoprative CA125 as a prognostic factor in stage I epithelial ovarian cancer. APMIS, 114, 358-63.
  29. Rodriguez M, Nguyen HN, Averette HE, et al (1994). National survey of ovarian carcinoma XII. Epithelial ovarian malignancies in women less than or equal to 25 years of age. Cancer, 73, 1245-50.<1245::AID-CNCR2820730419>3.0.CO;2-5
  30. Saeed S, Akram, M (2012). Epithelial ovarian cancer: epidemiology and clinicopathological features. Profesional Med J, 19, 1040-5.
  31. Segelman J, Floter-Radestad A, Hellborg H. Sjovall A, Martling A (2010). Epidemiology and prognosis of ovarian metastases in colorectal cancer. Br J Surg, 97, 1704-9.
  32. Shawky AEA, El-Hafez AA, El-Tantawy, Hamdy R (2014). No association between BRCA1 immunohistochemical expression and tumor grade, stage or overall survival in platinum-tested epithelial ovarian cancer patients. Asian Pac J Cancer Prev, 15, 4275-9.
  33. Thrall M, Gallion, HH, Kryscioz R, et al (2006). BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study. Int J Gynecol Cancer, 16, 166-71.
  34. Urban N (2003). Specific keynote: Ovarian cancer risk assessment and the potential for early detection. Gynecol Oncol, 88, 75-9.
  35. Winter III WE, Maxwell GL, Tian C, et al (2008). Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a gynecologic oncology group study. J Clin Oncol, 26, 83-9.
  36. Yang D, Khan S, Sun Y, et al (2011). Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA, 306, 1557-65.

Cited by

  1. Methylation Status and Expression of BRCA2 in Epithelial Ovarian Cancers in Indonesia vol.16, pp.18, 2016,