Clinicopathological Significance of BRCA1 Promoter Hypermethylation in Thai Breast Cancer Patients

  • Published : 2015.01.22


Breast cancer susceptibility gene 1 (BRCA1), mapped on chromosome 17q21, is implicated in the mechanisms of cellular DNA repair. Inactivation of this gene is involved in the development of many human cancers, including breast cancer. This study aimed to investigate the prognostic value of BRCA1 promoter hypermethylation and expression in breast cancer cases. Sixty-one breast cancers were examined for BRCA1 hypermethylation by methylation-specific polymerase chain reaction (PCR), and 45 paired normal breast tissues were analyzed for altered BRCA1 mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Aberrant methylation status in BRCA1 was detected in 15 of 61 cases (24.6%), while reduced expression was found in 7 of 45 (15.6%). BRCA1 hypermethylation was statistically associated with tumor grade III (p=0.04), a high frequency of stage IIB (p=0.02), and triple-negative phenotype (OR= 3.64, 95%CI =1.1-12.3, p=0.03). Our findings indicated that BRCA1 promoter hypermethylation is a useful prognostic marker for breast cancer.


  1. Bal A, Verma S, Joshi K, et al (2012). BRCA1-methylated sporadic breast cancers are BRCA-like in showing a basal phenotype and absence of ER expression. Virchows Arch, 461, 305-12.
  2. Baldwin RL, Nemeth E, Tran H, et al (2000). BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res, 60, 5329-33.
  3. Ben Gacem R, Hachana M, Ziadi S, et al (2012). Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients. Cancer Epidemiol, 36, 190-7.
  4. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, et al (2006). Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res, 8,38.
  5. Camirand A, Fadhil I, Luco AL, et al (2013). Enhancement of taxol, doxorubicin and zoledronate anti-proliferation action on triple-negative breast cancer cells by a PTHrP blocking monoclonal antibody. Am J Cancer Res, 3, 500-8.
  6. Cropp CS, Champeme MH, Lidereau R, et al (1993). Identification of three regions on chromosome 17q in primary human breast carcinomas which are frequently deleted. Cancer Res, 53, 5617-9.
  7. Ford D, Easton DF, Bishop DT, et al (1994). Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet, 343, 692-5.
  8. Galizia E, Giorgetti G, Piccinini G, et al (2010). BRCA1 expression in triple negative sporadic breast cancers. Anal Quant Cytol Histol, 32, 24-9.
  9. 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.
  10. Matros E, Wang ZC, Lodeiro G, et al (2005). BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat, 91, 179-86.
  11. Miki Y, Swensen J, Shattuck-Eidens D, et al (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266, 66-71.
  12. Miller SA, Dykes DD, Polesky HF, (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 16, 1215.
  13. Mirza S, Sharma G, Prasad CP, et al (2007). Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. Life Sci, 81, 280-7.
  14. Niwa Y, Oyama T, Nakajima T, (2000). BRCA1 expression status in relation to DNA methylation of the BRCA1 promoter region in sporadic breast cancers. Jpn J Cancer Res, 91, 519-26.
  15. Pal R, Srivastava N, Chopra R, et al (2010). Investigation of DNA damage response and apoptotic gene methylation pattern in sporadic breast tumors using high throughput quantitative DNA methylation analysis technology. Mol Cancer, 23, 303.
  16. Paluszczak J, Baer-Dubowska W, (2006). Epigenetic diagnostics of cancer--the application of DNA methylation markers. J Appl Genet, 47, 365-75.
  17. Ralhan R, Kaur J, Kreienberg R, et al (2007). Links between DNA double strand break repair and breast cancer: accumulating evidence from both familial and nonfamilial cases. Cancer Lett, 248, 1-17.
  18. Rice JC, Ozcelik H, Maxeiner P, et al (2000). Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis, 21, 1761-5.
  19. Rosen EM, (2013). BRCA1 in the DNA damage response and at telomeres. Front Genet, 21,85.
  20. Saito H, Inazawa J, Saito S, et al (1993). Detailed deletion mapping of chromosome 17q in ovarian and breast cancers: 2-cM region on 17q21.3 often and commonly deleted in tumors. Cancer Res, 53, 3382-5.
  21. Sharma G, Mirza S, Parshad R, et al (2010). Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci, 87, 83-91.
  22. Sourvinos G, Spandidos DA, (1998). Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. Biochem Biophys Res Commun, 245, 75-80.
  23. Stefansson OA, Jonasson JG, Olafsdottir K, et al (2011). CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer. Epigenetics, 6, 638-49.
  24. Thompson ME, Jensen RA, Obermiller PS, et al (1995). Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet, 9, 444-50.
  25. Wei M, Grushko TA, Dignam J, et al (2005). BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. Cancer Res, 65, 10692-9.