Abstract
Ovarian malignancy is diagnosed in nearly a fourth of a million women internationally every year. Methylation of RASSF1A tumor suppressor gene prompts its inactivation in diseases. In this study, the RASSF1A promoter methylation was detected by methylated-specific PCR and investigated serum RASSF1A protein level through enzyme-linked immunosorbant assay in 160 Egyptian patients with ovarian cancer and 160 healthy controls. The present work proved that there was a higher frequency of RASSF1A methylation and a decrease in its serum level in patients with ovarian cancer compared to controls as well as in the high-grade tumor patients compared to low grade ones and also in advanced ovarian tumor stage compared to early stages. Our study exhibited that RASSF1A promoter hypermethylation and its protein levels may be a reliable and sensitive tool for diagnosing and monitoring of ovarian malignancy patients.
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Ozdemir, F., Altinisik, J., Karateke, A., Coksuer, H., & Buyru, N. (2012). Methylation of tumor suppressor genes in ovarian cancer. ExpTher Med, 4, 1092–1096.
Zhang, Y., Guo, B., & Bi, R. (2012). Ovarian cancer: biomarker proteomic diagnosis in progress. Applied Biochemistry and Biotechnology, 168, 910–916.
American Cancer Society. (2007). Cancer facts & figures. Atlanta: The Society.
Clarke-Pearson, D. L. (2009). Clinical practices. Screening for ovarian cancer. The New England Journal of Medicine, 361, 170–177.
Board, R. E., Knight, L., Greystoke, A., Blackhall, F. H., Hughes, A., Dive, C., & Ranson, M. (2008). DNA methylation in circulating tumour DNA as a biomarker for cancer. Biomarker Insights, 2, 307–319.
Aggarwal, M. R., Kumar, A., & Shrivastava, A. (2015). Natural compounds: DNA methyltransferase inhibitors in oral squamous cell carcinoma. Applied Biochemistry and Biotechnology, 177, 577–594.
Sepulveda, A. R., Jones, D., Ogino, S., Samowitz, W., Gulley, M. L., Edwards, R., Levenson, V., Pratt, V. M., Yang, B., Nafa, K., Yan, L., & Vitazka, P. (2009). CpG methylation analysis–current status of clinical assays and potential applications in molecular diagnostics: a report of the Association for Molecular Pathology. The Journal of Molecular Diagnostics, 11, 266–278.
Barton, C. A., Hacker, N. F., Clark, S. J., & O’Brien, P. M. (2008). DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecologic Oncology, 109, 129–139.
Ibanez de Caceres, I., Battagli, C., Esteller, M., Herman, J. G., Dulaimi, E., Edelson, M. I., Bergman, C., Ehya, H., Eisenberg, B. L., & Cairns, P. (2004). Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Research, 64, 6476–6481.
Melnikov, A., Scholtens, D., Godwin, A., & Levenson, V. (2009). Differential methylation profile of ovarian cancer in tissues and plasma. The Journal of Molecular Diagnostics, 11, 60–65.
Su, H. Y., Lai, H. C., Lin, Y. W., Chou, Y. C., Liu, C. Y., & Yu, M. H. (2009). An epigenetic markerpanel for screening and prognostic prediction of ovarian cancer. International Journal of Cancer, 124, 387–393.
Leon, S. A., Shapiro, B., Sklaroff, D. M., & Yaros, M. J. (1977). Free DNA in the serum of cancer patients and the effect of therapy. Cancer Research, 37, 646–650.
Chmelarova, M., Dvorakova, E., Spacek, J., Laco, J., & Palicka, V. (2013). Importance of promoter methylation of GATA4 gene in epithelial ovarian cancer. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic, 157(4), 294–297.
Hesson, L. B., Cooper, W. N., & Latif, F. (2007). The role of RASSF1A methylation in cancer. Disease Markers, 23, 73–87.
Lee, M. G., Kim, H. Y., Byun, D. S., Lee, S. J., Lee, C. H., Kim, J. I., Chang, S. G., & Chi, S. G. (2001). Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. Cancer Research, 61, 6688–6692.
Donninger, H., Vos, M. D., & Clark, G. J. (2007). The RASSF1A tumor suppressor. Journal of Cell Science, 120, 3163–3172.
Dammann, R., Schagdarsurengin, U., Seidel, C., Strunnikova, M., Rastetter, M., Baier, K., & Pfeifer, G. P. (2005). The tumor suppressor RASSF1A in human carcinogenesis: an update. Histology and Histopathology, 20, 645–663.
Pfeifer, G. P., Dammann, R., & Tommasi, S. (2010). RASSF proteins. Current Biology, 20, R344–R345.
Ren, J., Singh, B. N., Huang, Q., Li, Z., Gao, Y., Mishra, P., Hwa, Y. L., Li, J., Dowdy, S. C., & Jiang, S. W. (2011). DNA hypermethylation as a chemotherapy target. Cellular Signalling, 23(7), 1082–1093.
Landen, C. N., Birrer, M. J., & Sood, A. K. (2008). Early events in the pathogenesis of epithelial ovarian cancer. Journal of Clinical Oncology, 26, 995–1005.
Huang, Z., Wen, Y., Shandilya, R., Marks, J. R., Berchuck, A., & Murphy, S. K. (2006). High through put detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. Nucleic Acids Research, 34, 555–563.
Harden, S. V., Tokumaru, Y., Westra, W. H., Goodman, S., Ahrendt, S. A., Yang, S. C., & Sidransky, D. (2003). Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clinical Cancer Research, 9, 1370–1375.
Jones, P. A., & Laird, P. W. (1999). Cancer epigenetics comes of age. Nature Genetics, 21, 163–167.
Zhao, M., Sun, J., & Zhao, Z. (2012). Distinct and competitive regulatory patterns of tumor suppressor genes and oncogenes in ovarian cancer. PLoS One, 7, e44175.
Jones, P. A., & Baylin, S. B. (2002). The fundamental role of epigenetic events in cancer. Nature Reviews. Genetics, 3, 415–428.
Xing, B. L., Li, T., Tang, Z. H., Jiao, L., Ge, S. M., Qiang, X., & OuYang, J. (2015). Cumulative methylation alternations of gene promoters and protein markers for diagnosis of epithelial ovarian cancer. Genetics and Molecular Research, 4, 4532–4540.
Montavon, C., Gloss, B. S., Warton, K., Barton, C. A., Statham, A. L., Scurry, J. P., Tabor, B., Nguyen, T. V., Qu, W., Samimi, G., Hacker, N. F., Sutherland, R. L., Clark, S. J., & O’Brien, P. M. (2012). Prognostic and diagnostic significance of DNA methylation patterns in high grade serous ovarian cancer. Gynecologic Oncology, 124, 582–588.
Bhagat, R., Chadaga, S., Premalata, C. S., Ramesh, G., Pallavi, V. R., & Krishnamoorthy, L. (2012). Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development. Cellular Oncology, 35, 473–479.
Zhang, J., Xing, B., Song, J., Zhang, F., Nie, C., Jiao, L., Liu, L., Lv, F., & Wang, S. (2014). Associated analysis of DNA methylation for cancer detection using CCP-based FRET technique. Analytical Chemistry, 86, 346–350.
Zuberi, M., Mir, R., Dholariya, S., Najar, I., Yadav, P., Javid, J., Guru, S., Mirza, M., Gandhi, G., Khurana, N., Ray, P. C., & Saxena, A. (2014). RASSF1 and PTEN promoter hypermethylation influences the outcome in epithelial ovarian cancer. Clin Ovarian and Other Gynecol Cancer, 7, 33–39.
Matoo, A. A., Khan, H., Wani, H. A., Bhat, A. A., Habib, M., Bashir, H., Farooq, R., Rasheed, T., Naikoo, N. A., Zargar, M. A., Massood, A., & Majid, S. (2013). RAS association domain isoform a gene (RASSF1A) hypermethylation in ovarian cancer patients of Kashmir Valley. J Pak Med Stud, 3, 87–91.
Shi, H., Li, Y., Wang, X., Lu, C., Yang, L., Gu, C., Xiong, J., Huang, Y., Wang, S., & Lu, M. (2013). Association between RASSF1A promoter methylation and ovarian cancer: a meta-analysis. PLoS One, 8, e76787.
Fu, L. J., & Zhang, S. L. (2015). Expression of RASSF1A in epithelial ovarian cancers. Eur Rev Med PharmacolSci, 19, 813–817.
Pan, Y. M., Wu, Y. Z., Shi, Y. F., & Zhu, Z. Q. (2015). Methylation of tumor suppressor gene RASSF1A and BRCA1 in primary epithelial ovarian cancer. Scientific Research and Essays, 5(24), 3939–3944.
Giannopoulou, L., Chebout, I. I., Pavlakis, K., Kasimir-Bauer, S., & Lianidou, S. E. (2017). RASSF1A promoter methylation in high-grade serous ovarian cancer: a direct comparison study in primary tumors, adjacent morphologically tumor cell-free tissues and paired circulating tumor DNA. Oncotarget, 8, 21429–21443.
Gobel, G., Auer, D., Gaugg, I., Schneitter, A., Lesche, R., Muller-Holzner, E., Marth, C., & Daxenbichler, G. (2011). Prognostic significance of methylated RASSF1A and PITX2 genes in blood- and bone marrow plasma of breast cancer patient. Breast Cancer Research and Treatment, 130, 109–117.
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The ethics committee of Zagazig University approved this study (REC number Zu- 123432 I).
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Rezk, N.A., Mohamed, R.H., Alnemr, A.A. et al. Promoter Methylation of RASSF1A Gene in Egyptian Patients with Ovarian Cancer. Appl Biochem Biotechnol 185, 153–162 (2018). https://doi.org/10.1007/s12010-017-2648-4
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DOI: https://doi.org/10.1007/s12010-017-2648-4