BRCA1 promoter hypermethylation in sporadic epithelial ovarian carcinoma: Association with low expression of BRCA1, improved survival and co-expression of DNA methyltransferases

Abstract

The breast cancer susceptibility gene 1 (BRCA1) inactivation in sporadic epithelial ovarian carcinoma (EOC) is common and low BRCA1 expression is associated with promoter hypermethylation. The clinical validation of BRCA1 methylation as a prognostic marker in EOC remains unresolved. The aim of the present study was to determine the aberrant promoter methylation of BRCA1 in benign and malignant ovarian tumor tissues, to establish the association with the clinicopathological significance and the prognostic value. Additionally, the contribution of DNA methyltransferase (DNMT) expression to BRCA1 promoter hypermethylation was determined. The rate of BRCA1 methylation was observed to be 35.2% (50/142) in the EOCs; however, no methylation (0/32) was observed in the benign tumors. BRCA1 methylation was significantly associated with the downregulation of BRCA1 expression (P<0.001) and the frequency of BRCA1 methylation was greater in the carcinomas of patients whose tumor was bilateral than that of patients with a unilateral carcinoma (P=0.015). BRCA1 methylation was significantly associated with the preoperative serum carbohydrate antigen-125 level (P=0.013), improved overall survival (P=0.005) and disease-free survival (P=0.007). In addition, a significant correlation was observed between the co-expression of DNMTs and the methylation status of BRCA1. Thus, the present study provided support for BRCA1 promoter hypermethylation as a prognostic marker for survival in sporadic EOC, and co-expression of DNMTs was observed to contribute to BRCA1 promoter hypermethylation.

Methylation Status and Immunohistochemistry of BRCA1 in Epithelial Ovarian Cancer

“…Chiang et al demonstrated survival disavantage in patients whose neoplasm were methylated at BRCA1 (Chiang et al, 2006). However, reported significant association between BRCA1 gene methylation and improved survival rate in patients with advanced stage (stage III-IV) (Bai et al, 2014). The inconsistency of these results may be due to the varying population and different environtment condition that were involved in the studies.…”

Aberrant promoter methylation of cancer-related genes in human breast cancer

“…BRCA1 , which is a typical tumor suppressor gene, contributes to the regulation of transcriptional activation, DNA repair, apoptosis, cell-cycle checkpoint control and chromosomal remodeling (28). A previous meta-analysis has provided evidence that BRCA1 methylation is associated with the poor survival of patients with BC (34).…”

“…The expression of BRCA1 and GSTP1 was evaluated using the semi-quantitative scoring criteria according to the staining intensity (0, negative; 1, weak; 2, moderate; and 3, strong) and the proportion of positive cells (0, positive in ≤5%; 1, positive in >5 and ≤25%; 2, positive in >25 and ≤50%; 3, positive in >50 and ≤80%; and 4, positive in >80% tumor cells). The two scores were multiplied together for each case and gene expression was subsequently graded as: 0, negative score; 1–4, weak expression score; 5–8, moderate expression score; and 9–12, strong expression score (28). …”

DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome

“…The low expressions of BRCA1 and BRCA2 genes have also been reported in solid tumours, such as epithelial ovarian carcinoma, prostate cancer and breast cancer 31 32. Using MLR analysis, we detected that decreased expression of BRCA2 was associated with an increased chance of developing hMDS with an OR of 12.…”