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Methylation profiles of the BRCA1 promoter in hereditary and sporadic breast cancer among Han Chinese

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Abstract

The development of breast cancer is a multistep process associated with complex changes in host gene expression patterns including inactivation of tumor suppressor genes and activation of oncogenes. Critically, hereditary predisposition plays a significant role in cancer susceptibility. However, mutation of the BRCA1 gene is found only in the minority of hereditary breast cancer, which indicates that there might be alternative, novel mechanisms contributing to inactivation of the BRCA1 gene. Studies have shown that aberrant methylation of genomic DNA plays an important role in carcinogenesis. The aim of this study was to investigate whether DNA methylation may be an alternative mechanism for the inactivation of BRCA1 as an epigenetic modification of the genome and whether hereditary breast cancer has a different BRCA1 methylation phenotype pattern than sporadic breast cancer. The pattern of CpG island methylation within the promoter region of BRCA1 was assessed by bisulfite sequencing DNA from peripheral blood cells of 72 patients with hereditary predisposition but without BRCA1 mutations and 30 sporadic breast cancer controls. The overall methylation level in patients with hereditary predisposition was significantly lower than that in the sporadic control group. However, patients with hereditary predisposition showed a significantly higher methylation susceptibility for the sites −518 when compared to controls. These results suggest that there might be different BRCA1 promoter methylation levels and patterns in sporadic and hereditary breast cancer in peripheral blood DNA. These findings may facilitate the early diagnosis of hereditary breast cancer.

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References

  1. Ahmedin J, Freddie B, Melissa M, Jacques F, Elizabeth W, David F. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  Google Scholar 

  2. James CR, Quinn JE, Mullan PB, Johnston PG, Harkin DP. BRCA1, a potential predictive biomarker in the treatment of breast cancer. Oncologist. 2007;12(2):142–50.

    Article  PubMed  CAS  Google Scholar 

  3. Pasche B. Recent advances in breast cancer genetics. Cancer Treat Res. 2008;141:1–10.

    Article  PubMed  Google Scholar 

  4. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.

    Article  PubMed  CAS  Google Scholar 

  5. Andrieu N, Goldgar DE, Easton DF, Rookus M, Brohet R, Antoniou AC. Pregnancies, breast-feeding, and breast cancer risk in the international BRCA1/2 carrier cohort study (IBCCS). J Natl Cancer Inst. 2006;98(8):535–44.

    Article  PubMed  Google Scholar 

  6. Gorski JJ, Kennedy RD, Hosey AM, Harkin DP. The complex relationship between BRCA1 and ERα in hereditary breast cancer. Clin Cancer Res. 2009;15(5):1514–8.

    Article  PubMed  CAS  Google Scholar 

  7. Xu X, Gammon MD, Zhang Y, et al. BRCA1 promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Res Treat. 2009;115(2):397–404.

    Article  PubMed  CAS  Google Scholar 

  8. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.

    Article  PubMed  CAS  Google Scholar 

  9. Brooks J, Cairns P, Zeleniuch-Jacquotte A. Promoter methylation and the detection of breast cancer. Cancer Causes Control. 2009;20(9):1539–50.

    Article  PubMed  Google Scholar 

  10. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21.

    Article  PubMed  CAS  Google Scholar 

  11. Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis. 2000;21(9):1761–5.

    Article  PubMed  CAS  Google Scholar 

  12. Attwood JT, Yung RL, Richardson BC. DNA methylation and the regulation of gene transcription. Cell Mol Life Sci. 2002;59(2):241–57.

    Article  PubMed  CAS  Google Scholar 

  13. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res. 2006;8(4):R38.

    Article  PubMed  Google Scholar 

  14. Suter CM, Martin DI, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet. 2004;36(5):497–501.

    Article  PubMed  CAS  Google Scholar 

  15. Suijkerbuijk KP, Fackler MJ, Sukumar S, et al. Methylation is less abundant in BRCA1-associated compared with sporadic breast cancer. Ann Oncol. 2008;19(11):1870–4.

    Article  PubMed  CAS  Google Scholar 

  16. Rice JC, Massey-Brown KS, Futscher BW. Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene. 1998;17(14):1807–12.

    Article  PubMed  CAS  Google Scholar 

  17. Honrado E, Osorio A, Milne RL, et al. Immunohistochemical classification of non-BRCA1/2 tumors identifies different groups that demonstrate the heterogeneity of BRCAX families. Mod Pathol. 2007;20(12):1298–306.

    Article  PubMed  CAS  Google Scholar 

  18. Ali AB, Iau PT, Sng JH. Cancer-specific methylation in the BRCA1 promoter in sporadic breast tumours. Med Oncol. 2010. [Epub ahead of print].

  19. Tapia T, Smalley SV, Kohen P, Muñoz A, Solis LM, Corvalan A. Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics. 2008;3(3):157–63.

    Article  PubMed  Google Scholar 

  20. Chen Y, Zhou J, Xu Y, Li Z, Wen X, Yao L, Xie Y, Deng D. BRCA1 promoter methylation associated with poor survival in Chinese patients with sporadic breast cancer. Cancer Sci. 2009;100:1663–7.

    Article  PubMed  CAS  Google Scholar 

  21. Matros E, Wang ZC, Lodeiro G, Miron A, Iglehart JD, Richardson AL. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat. 2005;91:179–86.

    Article  PubMed  CAS  Google Scholar 

  22. Zhao Z, Han L. CpG islands: algorithms and applications in methylation studies. Biochem Biophys Res Commun. 2009;382(4):643–5.

    Article  PubMed  CAS  Google Scholar 

  23. Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002;21(35):5400–13.

    Article  PubMed  CAS  Google Scholar 

  24. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 2000;16(4):168–74.

    Article  PubMed  CAS  Google Scholar 

  25. Zhu WG, Srinivasan K, Dai Z, Duan W, et al. Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21 (Cip1) promoter. Mol Cell Biol. 2003;23(12):4056–65.

    Article  PubMed  CAS  Google Scholar 

  26. Clark SJ, Harrison J, Molloy PL. Sp1 binding is inhibited by mCpmCpG methylation. Gene. 1997;195(1):67–71.

    Article  PubMed  CAS  Google Scholar 

  27. Watt F, Molloy PL. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev. 1988;2(9):1136–43.

    Article  PubMed  CAS  Google Scholar 

  28. Mancini DN, Rodenhiser DI, Ainsworth PJ, O’Malley FP, Singh SM, Xing W. CpG methylation within the 5′ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene. 1998;16(9):1161–9.

    Article  PubMed  CAS  Google Scholar 

  29. Catteau A, Joanna R. Morris. BRCA1 methylation: a significant role in tumour development. Semin Cancer Biol. 2002;12(5):359–71.

    Article  PubMed  CAS  Google Scholar 

  30. Hitchins MP, Ward RL. Erasure of MLH1 methylation in spermatozoa- implications for epigenetic inheritance. Nat Genet. 2007;39:1289.

    Article  PubMed  CAS  Google Scholar 

  31. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27(5):351–7.

    Article  PubMed  CAS  Google Scholar 

  32. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet. 1998;19(3):219–20.

    Article  PubMed  CAS  Google Scholar 

  33. Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S. Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat. 2007;106(2):263–71.

    Article  PubMed  CAS  Google Scholar 

  34. Abreu PA, Dellamora-Ortiz G, Leão-Ferreira LR, et al. DNA mrthylation: a promising target for the twenty-first century. Expert Opin Ther Targets. 2008;12(8):1035–47.

    Article  PubMed  CAS  Google Scholar 

  35. Chen Y, Toland AE, McLennan J, et al. Lack of germ-line promoter methylation in BRCA1-negative families with familial breast cancer. Genet Test. 2006;10(4):281–4.

    Article  PubMed  CAS  Google Scholar 

  36. Yazici H, Terry MB, Cho YH, et al. Aberrant methylation of RASSF1A in plasma DNA before breast cancer diagnosis in the breast cancer family registry. Cancer Epidemiol Biomarkers Prev. 2009;18(10):2723–5.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to the insightful work provided by Dr. Yashuang Zhao and all of the fellows and students who gave me the possibility to complete this thesis. We thank Dr. Shihui Yu and Dr. QingBin Song for critical reading of the manuscript, graphics assistance and word processing assistance.

Conflict of interest

The authors declare that they have no competing financial interests.

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Authors and Affiliations

  1. Department of Breast Surgery, The Third Affiliated Hospital of Harbin Medical University, HaPing Road 158, Harbin, China

    Da Pang, Weinan Xue, Ming Shan, Yanbo Chen, Youxue Zhang, Guoqiang Zhang, Feng Liu & Dalin Li

  2. Institute of Cancer Prevention and Treatment, Harbin Medical University, BaoJian Road 6, Harbin, 150081, China

    Da Pang & Yanmei Yang

  3. Epidemiology Department, Harbin Medical University, BaoJian Road 157, Harbin, China

    Yashuang Zhao

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  1. Da Pang
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  2. Yashuang Zhao
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  3. Weinan Xue
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  4. Ming Shan
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  5. Yanbo Chen
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  7. Guoqiang Zhang
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  8. Feng Liu
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  9. Dalin Li
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  10. Yanmei Yang
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Correspondence to Da Pang or Yashuang Zhao.

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Pang, D., Zhao, Y., Xue, W. et al. Methylation profiles of the BRCA1 promoter in hereditary and sporadic breast cancer among Han Chinese. Med Oncol 29, 1561–1568 (2012). https://doi.org/10.1007/s12032-011-0100-0

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  • DOI: https://doi.org/10.1007/s12032-011-0100-0

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