ABCR  Vol.7 No.2 , April 2018
Detection of Promoter Hypermethylation of GSTP1 and CDH1 Genes and the Relationship of Histopathological Parameters of the Breast
Abstract: Background: Breast cancer is the most common cancer in women. Histopathology plays an important part in determining the treatment strategy for women with breast cancer. GSTP1 plays an important role in protecting cells from cytotoxic and carcinogenic agents and it is expressed in normal tissues at variable levels in different cell types. CDH1 plays a critical role for establishment and maintenance of polarity and differentiation of epithelium during the development period. Also, it plays an important role in signal transduction, differentiation, gene expression, cellmotility and inflammations. Methods: In this study the promoter methylation levels of GSTP1 and CDH1 gene which are associated with breast cancer were investigated by technique of Methylation Sensitive High Resolution Melting Analysis (MS-HRM). We analysed primary tumor core biopsies from 80 high-risk primary breast cancer patients (tumors ≥ 2 cm and/or lymphatic metastase and/or distant metastases and/or under 40 years). Also the patients histopathologic types were associated with the methylation levels. Results: In our study the promoter hypermethylation status was observed at different rates; GSTP1 and CDH1 hypermethylation frequencies were 82% and 95% respectively. The promoter hypermethylation levels of the genes were found to be significant with lymph node positivity, ER positivity and HER2/neu negativity. Conclusion: Our study is important as being the first study that analyzes association between histopathologic type and GSTP1 and CDH1 gene promotor methylation status in Turkish population.
Cite this paper: Eroglu, O. , Baysak, M. , Aras, B. , Cilingir, O. , Artan, S. (2018) Detection of Promoter Hypermethylation of GSTP1 and CDH1 Genes and the Relationship of Histopathological Parameters of the Breast. Advances in Breast Cancer Research, 7, 91-106. doi: 10.4236/abcr.2018.72006.

[1]   Etseller, M. and Herman, J.G. (2002) Cancer as an Epigenetic Disease: DNA Methylation and Chromatin Alterations in Human Tumours. The Journal of Pathology, 196, 1-7.

[2]   Esteller, M. (2005) Dormant Hypermethylated Tumor Suppressor Genes: Questions and Answers. The Journal of Pathology, 205, 172-180.

[3]   Bae, Y.K., Brown, A., Garrett, E., Bornman, D., Fackler, M.J., Sukumar, S., Herman, J.G. and Gabrielson, E. (2004) Hypermethylation in Histologically Distinct Classes of Breast Cancer. Clinical Cancer Research, 10, 5998-6005.

[4]   Isabelle, M. (2010) Glutathione S-Transferase pi (GSTP1). Atlas of Genetics and Cytogenetics in Oncology and Haematology, 14, 1181-1185.

[5]   Kim, E.K. and Sahin, A. (2005) E-Cadherin Expression Loss in T1 Invasive Ductal Carcinoma of Breast as a Predictive Marker for Lymph Node Metastasis. The Korean Journal of Pathology, 39, 187-191.

[6]   Lombaerts, M., Wezel, T.V., Philippo, K., Dierssen, J.W.F., Zimmerman, R.M.E., Oosting, J., Eijek, R.V., Eilers, P.H., Water, B.V.D., Cornelisse, C.J., et al. (2006) E-Cadherin Transcriptional Downregulation by Promoter Methylation But Not Mutation Is Related to Epithelial-To-Mesenchymal Transition in Breast Cancer Cell Line. British Journal of Cancer, 94, 661-671.

[7]   Wilson, B.A.R., Kaurah, P., Suriano, G., Leach, S., Senz, J., Grehan, N., Butterfield, Y.S.N., Jeyes, J., Schinas, J., Bacani, J., et al. (2004) Germline E-Cadherin Mutations in Hereditary Diffuse Gastric Cancer: Assessment of 42 New Families and Review of Genetic Screening Criteria. Journal of Medical Genetics, 41, 508-517.

[8]   Slaus, N.P. (2003) Tumor Suppressor Gene E-Cadherin and It’s Role in Normal and Malignant Cells. Cancer Cell International, 3, 1-7.

[9]   Goldstein, N.S., Bassi, D., Watts, J.C., Layfield, L.J., Yaziji, H. and Gown, A.M. (2001) E-Cadherin Reactivity of 95 Noninvasive Ductal and Lobular Lesions of the Breast. Implications for the Interpretation of Problematic Lesions. American Journal of Clinical Pathology, 115, 534-542.

[10]   Mastracci, T.L., Tjan, S., Bane, A.L., OMalley, P.F. and Andrulis, I.L. (2005) Ecadherin Alterations in Atypical Lobular Hyperplasia and Lobular Carcinoma Insitu of the Breast. Modern Pathology, 18, 741-751.

[11]   Tischoff, I. and Tannapfel, A. (2008) DNA Methylation in Hepatocellular Carcinoma. World Journal of Gastroenterology, 14, 1741-1748.

[12]   Maruyama, R, Toyooka, S., Toyooka, O.K., Harda, K. and Virmani, A.K. (2001) Aberrant Promoter Methylation Profile of Bladder Cancer and It’s Relationship to Clinicopathological Features. Cancer Research, 61, 8659-8663.

[13]   Yang, X., Yan, L. and Davidson, N.L. (2001) DNA Methylation in Breast Cancer. Endocrine Related Cancer, 8, 115-127.

[14]   Colot, V. and Rossignol, J.L. (1999) Eukaryotic DNA Methylation as an Evolutionary Device. BioEssays, 21, 402-411.<402::AID-BIES7>3.0.CO;2-B

[15]   Epstein, A.H., Conolly, J.L. and Gelman, R. (1989) The Predictors of Distant Relapse Following Conservative Surgery and Radiotherapy for Early Breast Cancer Are Similar to Those Following Mastectomy. International Journal Radiation Oncology Biology Physics, 17, 755-760.

[16]   Wojdacz, T.K. and Dobrovic, A. (2007) Methylation-Sensitive High Resolution Melting (MS-HRM): A New Approach for Sensitive and High-Throughput Assessment of Methylation. Nucleic Acids Research, 35, 6-41.

[17]   Wojdacz, T.K., Moller, T.H., Thestrup, B.B., Kristensen, L.S. and Hansen, L.L. (2010) Limitations and Advantages of MS-HRM and Bisulfite Sequencing for Single Locus Methylation Studies. Expert Review of Molecular Diagnostics, 10, 575-580.

[18]   Francis, G., Beadlet, G., Thomas, S. and Mengersen, K. (2206) Evalution of Estrogen and Progesterone Receptor Status in HER-2 Positive Breast Carcinomas and Correlation with Outcome. Pathology, 38, 391-398.

[19]   Putti, T.C., Abd El-Rehim, D.M. and Rakha, E. (2005) Etsrogen Receptor-Negative Breast Carcinomas: A Review of Morphology and Immunophenotypical Analysis. Modern Pathology, 18, 26-35.

[20]   Rakha, A.E., El Sayed, E.A., Green, R.A. and Lee, H.S.A. (2007) Prognostic Markers in Triple-Negative Breast Cancers. Cancer, 1, 109 p.

[21]   Lee, J.S. (2007) GSTP1 Promotor Hypermetylation Is an Early Event in Breast Carcinogenesis. Virchows Archiv, 450, 637-642.

[22]   Park, S.Y., Kim, B.H., Kim, J.H., Cho, N.Y., Choi, M. and Yu, E.J. (2007) Methylation Profiles of CpG Island Loci in Major Types of Human Cancers. Journal of Korean Medical Science, 22, 311-317.

[23]   Sunami, E., Shinozaki, M., Sim, M.S., Nguyen, S.L., Vu, A.T., Giuliano, A.E. and Hoon, D.S.B. (2008) Estrogen Receptor and HER2/Neu Satatus Affect Epigenetic Differences of Tumor-Related Genes in Primary Breast Tumors. Breast Cancer Research, 10, R46.

[24]   Shinozaki, M., Hoon, H.S., Giuliano, A.E., Hansen, N.M., Wang, H.J., Turner, R. and Taback, B. (2005) Distinct Hypermethylation Profile of Primary Breast Cancer Is Associated with Sentinel Lymph Node Metastasis. Clinical Cancer Research, 15, 2156-2162.