Skip to main content

Advertisement

SpringerLink
Log in

Promoter methylation of BRCA1 in the prognosis of breast cancer: a meta-analysis

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The inactivation of BRCA1 by epigenetic alterations is a critical event in breast tumorigenesis, which may potentially be used as a prognostic marker for patients with breast cancer. The present study systematically reviewed the promoter methylation of BRCA1 and its relationship to the clinical outcomes of breast cancer patients. We performed a meta-analysis following the PRISMA guideline. Relevant articles were identified by searching PubMed, Web of Science and Embase database until August 2013. The pooled hazard ratio (HR) and 95 % confidence interval (CI) were applied to estimate the effect of BRCA1 methylation. Random or fixed effect model was chosen based on the heterogeneity analysis. A total of 3,205 patients from nine eligible studies were included in the meta-analysis. BRCA1 methylation was found to be significantly correlated with a poor overall survival of breast cancer, with the combined HR (95 % CI) of 2.02 (1.35–3.03). After adjusting for potential confounders using the Cox regression model, the pooled HR (95 % CI) of BRCA1 methylation on patients’ overall survival was 1.38 (1.04–1.84). If we used the disease-free survival as the outcome, the combined HR (95 % CI) was 2.89 (1.73–4.83) for univariate analysis and 3.92 (95 % CI 1.49–10.32) for multivariate analysis, respectively. Subgroup analysis of specimen types revealed that the pooled HR (95 % CI) for overall survival was 1.48 (1.22–1.81) when using formalin-fixed paraffin-embedded (FFPE) specimen and 1.38 (0.16–11.84) when using fresh frozen tissues. As for the disease-free survival, the pooled HR (95 % CI) was 2.47 (1.33–4.58) when using FFPE specimen and 2.78 (1.47–5.28) when using fresh frozen tissues. As a conclusion, the present meta-analysis provides evidence that BRCA1 methylation is associated with a poor survival of breast cancer patients. Our findings underscore the clinical relevance of aberrant epigenetic alteration as a promising biomarker for the prognosis of human cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer J 127(12):2893–2917. doi:10.1002/ijc.25516

    Article  CAS  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Article  PubMed  Google Scholar 

  3. Mukherjee A, Rakha EA (2012) Integrating breast cancer genetics into clinical practice. Womens Health (Lond Engl) 8(1):99–112. doi:10.2217/whe.11.81

    Article  CAS  Google Scholar 

  4. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J, Richardson AL, Schnitt SJ, Schmitt FC, Tan PH, Tse GM, Badve S, Ellis IO (2010) Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res 12(4):207. doi:10.1186/bcr2607

    PubMed  Google Scholar 

  5. Baylin SB, Belinsky SA, Herman JG (2000) Aberrant methylation of gene promoters in cancer—concepts, misconcepts, and promise. J Natl Cancer Inst 92(18):1460–1461

    Article  PubMed  CAS  Google Scholar 

  6. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21(2):163–167. doi:10.1038/5947

    Article  PubMed  CAS  Google Scholar 

  7. Toh Y, Egashira A, Yamamoto M (2013) Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma. Gen Thorac Cardiovasc Surg 61(5):262–269. doi:10.1007/s11748-013-0235-3

    Article  PubMed  Google Scholar 

  8. Fang F, Turcan S, Rimner A, Kaufman A, Giri D, Morris LG, Shen R, Seshan V, Mo Q, Heguy A, Baylin SB, Ahuja N, Viale A, Massague J, Norton L, Vahdat LT, Moynahan ME, Chan TA (2011) Breast cancer methylomes establish an epigenomic foundation for metastasis. Sci Transl Med 3 (75):75ra25. doi:10.1126/scitranslmed.3001875

  9. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692. doi:10.1016/j.cell.2007.01.029

    Article  PubMed  CAS  Google Scholar 

  10. Cheol Kim D, Thorat MA, Lee MR, Cho SH, Vasiljevic N, Scibior-Bentkowska D, Wu K, Ahmad AS, Duffy S, Cuzick JM, Lorincz AT (2012) Quantitative DNA methylation and recurrence of breast cancer: a study of 30 candidate genes. Cancer Biomark 11(2–3):75–88. doi:10.3233/CBM-2012-0266

    PubMed  Google Scholar 

  11. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250(4988):1684–1689

    Article  PubMed  CAS  Google Scholar 

  12. Ralhan R, Kaur J, Kreienberg R, Wiesmuller L (2007) Links between DNA double strand break repair and breast cancer: accumulating evidence from both familial and nonfamilial cases. Cancer Lett 248(1):1–17. doi:10.1016/j.canlet.2006.06.004

    Article  PubMed  CAS  Google Scholar 

  13. Chen Y, Zhou J, Xu Y, Li Z, Wen X, Yao L, Xie Y, Deng D (2009) BRCA1 promoter methylation associated with poor survival in Chinese patients with sporadic breast cancer. Cancer Sci 100(9):1663–1667. doi:10.1111/j.1349-7006.2009.01225.x

    Article  PubMed  CAS  Google Scholar 

  14. Xu X, Gammon MD, Zhang Y, Bestor TH, Zeisel SH, Wetmur JG, Wallenstein S, Bradshaw PT, Garbowski G, Teitelbaum SL, Neugut AI, Santella RM, Chen J (2009) BRCA1 promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Res Treat 115(2):397–404. doi:10.1007/s10549-008-0075-5

    Article  PubMed  CAS  Google Scholar 

  15. Khan SI, Aumsuwan P, Khan IA, Walker LA, Dasmahapatra AK (2012) Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome. Chem Res Toxicol 25(1):61–73. doi:10.1021/tx200378c

    Article  PubMed  CAS  Google Scholar 

  16. Hsu NC, Huang YF, Yokoyama KK, Chu PY, Chen FM, Hou MF (2013) Methylation of BRCA1 promoter region is associated with unfavorable prognosis in women with early-stage breast cancer. PLoS One 8(2):e56256. doi:10.1371/journal.pone.0056256

    Article  PubMed  CAS  Google Scholar 

  17. Van De Voorde L, Speeckaert R, Van Gestel D, Bracke M, De Neve W, Delanghe J, Speeckaert M (2012) DNA methylation-based biomarkers in serum of patients with breast cancer. Mutat Res 751(2):304–325. doi:10.1016/j.mrrev.2012.06.001

    Article  Google Scholar 

  18. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. doi:10.1371/journal.pmed.1000097

    Article  PubMed  Google Scholar 

  19. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16. doi:10.1186/1745-6215-8-16

    Article  PubMed  Google Scholar 

  20. DerSimonian R (1996) Meta-analysis in the design and monitoring of clinical trials. Stat Med 15(12):1237–1248; discussion 1249–1252. doi:10.1002/(SICI)1097-0258(19960630)15:12<1237::AID-SIM301>3.0.CO;2-N

  21. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. doi:10.1136/bmj.327.7414.557

    Article  PubMed  Google Scholar 

  22. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    PubMed  CAS  Google Scholar 

  23. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  PubMed  CAS  Google Scholar 

  24. Bax L, Ikeda N, Fukui N, Yaju Y, Tsuruta H, Moons KG (2009) More than numbers: the power of graphs in meta-analysis. Am J Epidemiol 169(2):249–255. doi:10.1093/aje/kwn340

    Article  PubMed  Google Scholar 

  25. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127(9):820–826

    Article  PubMed  CAS  Google Scholar 

  26. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  PubMed  CAS  Google Scholar 

  27. Xu Y, Diao L, Chen Y, Liu Y, Wang C, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Deng D, Narod SA, Xie Y (2013) Promoter methylation of BRCA1 in triple-negative breast cancer predicts sensitivity to adjuvant chemotherapy. Ann Oncol 24(6):1498–1505. doi:10.1093/annonc/mdt011

    Article  PubMed  CAS  Google Scholar 

  28. Sharma G, Mirza S, Parshad R, Srivastava A, Gupta SD, Pandya P, Ralhan R (2010) Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci 87(3–4):83–91. doi:10.1016/j.lfs.2010.05.001

    Article  PubMed  CAS  Google Scholar 

  29. Sharma G, Mirza S, Yang YH, Parshad R, Hazrah P, Datta Gupta S, Ralhan R (2009) Prognostic relevance of promoter hypermethylation of multiple genes in breast cancer patients. Cell Oncol 31(6):487–500. doi:10.3233/CLO-2009-0507

    PubMed  CAS  Google Scholar 

  30. Karray-Chouayekh S, Trifa F, Khabir A, Boujelbane N, Sellami-Boudawara T, Daoud J, Frikha M, Gargouri A, Mokdad-Gargouri R (2009) Clinical significance of epigenetic inactivation of hMLH1 and BRCA1 in Tunisian patients with invasive breast carcinoma. J Biomed Biotechnol 2009:369129. doi:10.1155/2009/369129

    PubMed  Google Scholar 

  31. Jing F, Jun L, Yong Z, Wang Y, Fei X, Zhang J, Hu L (2008) Multigene methylation in serum of sporadic Chinese female breast cancer patients as a prognostic biomarker. Oncology 75(1–2):60–66. doi:10.1159/000155145

    Article  PubMed  CAS  Google Scholar 

  32. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353(17):1784–1792. doi:10.1056/NEJMoa050518

    Article  PubMed  CAS  Google Scholar 

  33. Hayes DF, Isaacs C, Stearns V (2001) Prognostic factors in breast cancer: current and new predictors of metastasis. J Mammary Gland Biol Neoplasia 6(4):375–392

    Article  PubMed  CAS  Google Scholar 

  34. Ronneberg JA, Fleischer T, Solvang HK, Nordgard SH, Edvardsen H, Potapenko I, Nebdal D, Daviaud C, Gut I, Bukholm I, Naume B, Borresen-Dale AL, Tost J, Kristensen V (2011) Methylation profiling with a panel of cancer related genes: association with estrogen receptor, TP53 mutation status and expression subtypes in sporadic breast cancer. Mol Oncol 5(1):61–76. doi:10.1016/j.molonc.2010.11.004

    Article  PubMed  CAS  Google Scholar 

  35. Kennedy RD, Quinn JE, Johnston PG, Harkin DP (2002) BRCA1: mechanisms of inactivation and implications for management of patients. Lancet 360(9338):1007–1014. doi:10.1016/S0140-6736(02)11087-7

    Article  PubMed  CAS  Google Scholar 

  36. Stefansson OA, Villanueva A, Vidal A, Marti L, Esteller M (2012) BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer. Epigenetics 7(11):1225–1229. doi:10.4161/epi.22561

    Article  PubMed  CAS  Google Scholar 

  37. Krasteva ME, Bozhanov SS, Antov GG, Gospodinova ZI, Angelov SG (2012) Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status. Neoplasma 59(1):85–91

    Article  PubMed  CAS  Google Scholar 

  38. Jiang Y, Cui L, Chen WD, Shen SH, Ding LD (2012) The prognostic role of RASSF1A promoter methylation in breast cancer: a meta-analysis of published data. PLoS One 7(5):e36780. doi:10.1371/journal.pone.0036780

    Article  PubMed  CAS  Google Scholar 

  39. Hamilton MG, Roldan G, Magliocco A, McIntyre JB, Parney I, Easaw JC (2011) Determination of the methylation status of MGMT in different regions within glioblastoma multiforme. J Neurooncol 102(2):255–260. doi:10.1007/s11060-010-0307-5

    Article  PubMed  CAS  Google Scholar 

  40. Wu TL, Zhang D, Chia JH, Tsao K, Sun CF, Wu JT (2002) Cell-free DNA: measurement in various carcinomas and establishment of normal reference range. Clin Chim Acta 321(1–2):77–87

    Article  PubMed  CAS  Google Scholar 

  41. Kohler C, Barekati Z, Radpour R, Zhong XY (2011) Cell-free DNA in the circulation as a potential cancer biomarker. Anticancer Res 31(8):2623–2628

    PubMed  CAS  Google Scholar 

  42. Ignatiadis M, Reinholz M (2011) Minimal residual disease and circulating tumor cells in breast cancer. Breast Cancer Res 13(5):222. doi:10.1186/bcr2906

    Article  PubMed  CAS  Google Scholar 

  43. Dumitrescu RG (2012) Epigenetic markers of early tumor development. Methods Mol Biol 863:3–14. doi:10.1007/978-1-61779-612-8_1

    Article  PubMed  CAS  Google Scholar 

  44. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265(5181):2088–2090

    Article  PubMed  CAS  Google Scholar 

  45. Ben Gacem R, Hachana M, Ziadi S, Amara K, Ksia F, Mokni M, Trimeche M (2012) Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients. Cancer Epidemiol 36(2):190–197. doi:10.1016/j.canep.2011.09.001

    Article  PubMed  CAS  Google Scholar 

  46. Nasir A, Shackelford RE, Anwar F, Yeatman TJ (2009) Genetic risk of breast cancer. Minerva Endocrinol 34(4):295–309

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study is supported by the National Natural Science Foundation of China (81172268, 81172501), Key University Science Research Project of Jiangsu Province (12KJA330001), and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China

    Liang Wu, Ruobing Xu, Simin Zhang, Xianzhen Peng, Yan Feng & Jianming Wang

  2. Department of Breast, Nanjing Maternity and Child Health Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

    Fengliang Wang & Cheng Lu

Authors
  1. Liang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fengliang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruobing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianzhen Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jianming Wang or Cheng Lu.

Additional information

Liang Wu and Fengliang Wang have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, L., Wang, F., Xu, R. et al. Promoter methylation of BRCA1 in the prognosis of breast cancer: a meta-analysis. Breast Cancer Res Treat 142, 619–627 (2013). https://doi.org/10.1007/s10549-013-2774-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-013-2774-9

Keywords

Search

Navigation