Differences in p16 gene methylation and expression in benign and malignantovarian tumors

Objective. The aim of this study was to test the hypothesis that DNA methyl ation is important for silencing the p16 tumor suppressor gene in ovarian e pithelial tumors and to compare the prevalence of this mechanism among diff erent ovarian epithelial tumor subtypes. Method. Methylation-specific PCR was used to analyze the p16 gene for DNA m ethylation in 20 ovarian cystadenomas, 15 low malignant potential (LMP) tum ors, and 37 carcinomas, p16 expression was determined immunohistochemically in 58 of these tumors (16 cystadenomas, 13 LMP tumors, 29 carcinomas). Dif ferences in methylation or expression rates between specific tumor subgroup s 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 c ystadenomas, 4 of 13 LMP tumors, and 22 of 29 carcinomas (P [LMPs versus ca rcinomas] = 0.01) and correlated with methylation changes in LMP tumors (P = 0.05), p16 expression was correlated with mucinous differentiation in cys tadenomas (P = 0.001), Conclusion. p16 silencing may be important for the development of ovarian c arcinomas and a subset of LMP tumors. Changes in DNA methylation may be mor e important for inactivation of this gene (and perhaps other tumor suppress or genes) in LMP tumors, which lack many of the alternative mechanisms pres ent in carcinomas. p16 expression is primarily related to mucinous differen tiation in cystadenomas, (C) 1999 Academic Press.