Differences in p16 gene methylation and expression in benign and malignant ovarian tumors.

OBJECTIVE: The aim of this study was to test the hypothesis that DNA methylation is important for silencing the p16 tumor suppressor gene in ovarian epithelial tumors and to compare the prevalence of this mechanism among different ovarian epithelial tumor subtypes. METHOD: Methylation-specific PCR was used to analyze the p16 gene for DNA methylation in 20 ovarian cystadenomas, 15 low malignant potential (LMP) tumors, and 37 carcinomas. p16 expression was determined immunohistochemically in 58 of these tumors (16 cystadenomas, 13 LMP tumors, 29 carcinomas). Differences in methylation or expression rates between specific tumor subgroups were examined by Fisher's exact test. RESULTS: Fragments from the distal promoter and beginning of the first exon of the p16 gene were both methylated in 5 of 15 (33%) LMP tumors compared to 2 of 37 (5%) carcinomas (P = 0. 02). Those sites were also methylated in 5 of 20 (25%) cystadenomas. Lack of p16 expression was present in 7 of 16 cystadenomas, 4 of 13 LMP tumors, and 22 of 29 carcinomas (P [LMPs versus carcinomas] = 0. 01) and correlated with methylation changes in LMP tumors (P = 0.05). p16 expression was correlated with mucinous differentiation in cystadenomas (P = 0.001). CONCLUSION: p16 silencing may be important for the development of ovarian carcinomas and a subset of LMP tumors. Changes in DNA methylation may be more important for inactivation of this gene (and perhaps other tumor suppressor genes) in LMP tumors, which lack many of the alternative mechanisms present in carcinomas. p16 expression is primarily related to mucinous differentiation in cystadenomas.

Biology of ovarian cancer.

Although ovarian carcinomas are thought to arise from the ovarian surface mesothelial layer, the possibility that they develop from müllerian remnants within paraovarian tissues merits further consideration. Molecular genetic studies suggest that ovarian cystadenomas, low malignant potential tumors, and carcinomas are not part of a disease continuum but do represent separate disease entities. Recent advances in our understanding of the molecular genetic changes associated with ovarian epithelial tumor development can be summarized in a working genetic model for ovarian tumorigenesis, which can provide a framework for further studies. Certain molecular changes, such as telomerase expression and alterations in DNA methylation levels, are associated with both tumors of low malignant potential and carcinomas but not with cystadenomas. Mutations in the p53 gene and the development of multiple losses of heterozygosity are specific for the malignant phenotype. The nature of the specific chromosomes affected by the latter losses in a given tumor dictates its biologic aggressiveness.