Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas

Abstract

The newly identified 3p21.3 tumor suppressor gene RASSF1A is inactivated by hypermethylation in variable solid tumors, including those of the lung, breast, prostate, kidney, and ovary. The purpose of this study was to evaluate the methylation status of RASSF1A in various types and stages of ovarian epithelial tumors. We analyzed the DNA methylation status of ovarian tumors using methylation-specific polymerase chain reaction in 54 frozen ovarian tumor tissues and in 97 cases of archival ovarian serous epithelial tumors using a microdissection procedure. Hypermethylation statuses were examined vs clinicopathologic findings. RASSF1A promoter methylation rates in the various types of fresh ovarian tissues were as follows: serous cystadenoma (1/5), serous tumor of borderline malignancy (2/7), serous adenocarcinoma (4/10), mucinous cystadenoma (0/5), mucinous tumor of borderline malignancy (2/7), mucinous adenocarcinoma (3/6), transitional-cell carcinoma (1/3), clear-cell carcinoma (3/3), and malignant müllerian mixed tumor (3/3). In archived serous tumor tissues, RASSF1A promoter hypermethylation was detected in serous cystadenoma (1/6, 16.6%), serous tumor of borderline malignancy (20/41, 48.8%), and in serous adenocarcinoma (25/50, 50%). The status of RASSF1A hypermethylation in borderline tumors was found to correlate statistically with the presence of microinvasion (p=0.002), peritoneal implant (p<0.001), and bilaterality (p=0.019). The RASSF1A promoter hypermethylation was frequently found in borderline tumors and carcinomas, suggesting that RASSF1A promoter hypermethylation may be a useful molecular marker for the early detection of ovarian tumors.

Promoter hypermethylation patterns in fallopian tube epithelium of BRCA1 and BRCA2 germ line mutation carriers

“…RASSF1 (Makarla et al 2005, Choi et al 2006, Bol et al 2010, APC (Rathi et al 2002, Makarla et al 2005, CDH13 (Makarla et al 2005, Bol et al 2010, CDH1 (Rathi et al 2002) and GSTP1 (Makarla et al 2005, Bol et al 2010, which showed an increased methylation frequency in FTC compared with control tissue in this study, have previously been reported in ovarian cancer and not in its precursors. Choi et al (2006) showed that RASSF1 was frequently methylated in borderline tumours and ovarian carcinoma and showed a significant correlation with the presence of peritoneal implants, micro-invasion and bilaterality. Interestingly, four genes that were only found in invasive ovarian cancer and not in non-invasive lesions or normal tissue, RASSF1, APC, MGMT and GSTP1 (Makarla et al 2005), showed exactly the same pattern in this study.…”

“…For ovarian cancer, methylation has been shown in a number of tumour suppressor genes such as RASSF1, APC, PTEN, BRCA1, RARb, CDH13 and HIC1 (Rathi et al 2002, Makarla et al 2005, Choi et al 2006, Tam et al 2007. For FTC and its precursors, methylation has not yet been described.…”

Aberrant Methylation of RASSF2A in Tumors and Plasma of Patients with Epithelial Ovarian Cancer

“…Methylation of the RASSF1A promoter is described as an early and frequent event in tumorigenesis, thus RASSF1A can serve as a useful diagnostic marker in cancer screening (Dammann et al, 2000;Dammann et al, 2001;Liu WJ et al, 2013), including ovarian cancer (Agathanggelous et al, 2001;Yoon et al, 2001;Rathi et al, 2002;Ibanez et al, 2004;Makarla et al, 2005;Choi et al, 2006;Ma et al, 2009;BonDurant et al, 2011;Bhagat et al, 2012).…”

The correlation between the promotor methylation of TGF-?1 and chemoresistance in epithelial ovarian cancer

“…In this study, the doubling time of PTX-resistant cell lines was set as 36 to 48 h. So, treatment of 5-aza-dc should last for at least 96 h to fully exert its demethylation effect. According to some studies, the application of 5-aza-dc can restore the expression of hMLHI gene that is silenced by methylation, thus reversing the development of resistance of tumor cells to chemotherapeutics [12][13][14][15][16][17][18]. Staub et al [11] in a study on HSulf-I in ovarian cancer, found that abnormal expression of HSulf-I can induce a decrease in cytotoxicity caused by cobalt drugs, which might be due to the downregulation caused by abnormal methylation in promotor, while the drug resistance can be reversed after the treatment with methyltransferase inhibitor.…”