Our meta-analysis included eight eligible studies, with 428 ovarian cancers and 278 normal tissue samples and benign neoplasms. p16 promoter methylation was identified in 5.4 to 43.2% (median 27.86%) of ovarian cancers and 0 to 37.5% (median 15.8%) of normal tissue and benign neoplasms indicating that no significant association exists between p16 promoter methylation and epithelial ovarian cancer.
p14 absent expression was associated with malignant tumors (60 % positive) (p = 0.000), while 93 % and 94 % of benign and borderline tumors, respectively, were positive. p16 was positive in 94.6 % of carcinomas, 75 % of borderline and 45.7 % of benign tumors (p = 0.000). p53 negative staining was associated with benign tumors (2.9 % positive) (p = 0.016) but no difference was observed between borderline (16.7 %) and malignant tumors (29.7 %) (p = 0.560).
The presence of BRAF V600E and mitogen-activated protein kinase activation in a largely benign tumor supports the necessity for secondary events (e.g., p16 loss) in BRAF-driven oncogenesis.
Using a cutoff threshold based on receiver-operating characteristic analysis, 21 patients with ovarian cancer and three patients with benign tumors were considered positive for CDKN2A methylation while all patients with healthy ovaries were considered negative.
We propose that LMP1 acts at the early stages in carcinogenesis to promote the development of benign tumours and that early reduction of INK4a locus expression allows these lesions to expand in size.
Our results demonstrate that alterations of the INK4a-ARF locus are frequent and important events not only in the carcinogenesis of malignant, but also in benign tumors.