Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer

Abstract

Abstract. Endometrial cancer is a common gynecological malignancy with a good prognosis in early stages of the disease. The CpG island in the promoter region of tumorsuppressor genes are frequently methylated in various types of human cancers. In the present study, we examined the methylation status of the GSTP1, CDH1 and RASSF1A genes in endometrioid endometrial cancer (EEC), endometrial complex hyperplasia (EHP) and healthy endometrium with the aim to identify correlations between promoter hypermethylation, disease risk and clinicopathological parameters. A nested two-stage methylation-specific PCR (MSP) was performed to analyze the promoter CpG methylation status of GSTP1, CDH1 and RASSF1A genes in the population studied. A total of 92 subjects were initially included in the study of which 41 EEC, 19 EHP and 20 controls were processed for final analyses. A significant difference was found between the study groups and the presence of promoter CpG hypermethylation status in the GSTP1 (P<0.05) and RASSF1A (P<0.0001) genes. RASSF1A, GSTP1 and CDH1 gene promoter methylation was present in 85.4, 68.3 and 31.4% of EEC samples when compared to that in the controls with 30.0, 35.0 and 20.0%, respectively. CpG methylation of all three investigated tumor-suppressor genes was found in 12.2% of EEC patients, in 4.2% of EHP patients and in 3.7% of the controls, respectively. Positive findings for the promoter methylation of two investigated genes were found in 48.7% of EEC patients, 26.0% of EHP patients and in 18.5% of the controls. With regard to histopathological variables and CpG methylation, we found significant correlations between the RASSF1A and GSTP1 genes and higher tumor grade, deeper myometrial invasion and positive metastatic involvement of pelvic lymph nodes. No associations were noted between promoter hypermethylation of the CDH1 gene and biological features of the endometrial cancer cases. The results indicate that aberrant CpG methylation of the promoter region in the GSTP1 and RASSF1A tumor-suppressor genes is an important event in carcinogenesis of endometrial cancer and may have an impact on tumor aggressiveness. Finally, the present study suggests that epigenetic alterations may be of diagnostic value for the better clinical management of premalignant endometrial lesions.

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…Among the 24 TSGs studied, CDH13, RASSF1A, and GSTP1 were the most frequently methylated genes in endometrial hyperplasia and carcinoma. A recent study corroborated the findings of Nieminen et al, aberrant CpG methylation of the promoter region of GSTP1 and RASSF1A was found to be an important event in endometrial carcinogenesis and suggested to have an impact on tumor aggressiveness (Fiolka et al 2013).…”

DNA methylation as mechanism of apoptotic resistance development in endometrial cancer patients

“…Abnormalities in DNA methylation levels accompany early stages of endometrial carcinogenesis and may influence gene expression levels resulted in deregulation of apoptosis-associated genes (Tao and Freudenheim 2010;Ma and Gao 2014). Nowadays there are only a few scientific publications which have demonstrated DNA methylation status in apoptotic regulators during endometrial carcinogenesis and also during normal menstrual cycle (Zysman et al 2002;Salvesen et al 2004;Arafa et al 2008;Liao et al 2008;Pallares et al 2008;Fiolka et al 2013). In our study we investigated DNA methylation status of 22 apoptosisassociated genes in endometrial cancer tissue and healthy tissue using a commercially available methylation platform, EpiTect ® Methyl II Signature PCR Array (22) Kit (Qiagen).…”

Combined Effects Methylation of FHIT, RASSF1A and RARβ Genes on Non-Small Cell Lung Cancer in the Chinese Population

“…Methylation is major epigenetic modification in mammal, and changes in methylation patterns play a key role in tumor genesis with humans (Virmani et al, 2000;Dumitrescu et al, 2012;Fiolka et al, 2013). In particular, the promoter CpG island hypermethylation is closely related between inactivation and silencing, resulting in tumor suppressor loss of gene expression and X-chromosome inactivationmay, and affect development of carcinogenesis (Ki et al, 2008;Fiolka et al, 2013;Al-Temaimi et al, 2013). The aberrant promoter region methylation of tumor suppressor genes is associated with mechanism for carcinogenesis (Grote et al, 2006;Neyaz et al, 2008;Dumitrescu et al, 2012).…”