Loss of Expression of the p16 Tumor Suppressor Gene Is More Frequent in Advanced Ovarian Cancers Lacking p53 Mutations

Abstract

Objective. The aim of this study was to test the hypothesis that p53 mutations are less frequent in ovarian cancers with alterations in other genes that regulate G1 progression.Methods. Expression of G1 stimulatory (cyclins D1 and E, cdk4, Ki67) and inhibitory (p16, Rb, p27, p14) genes was analyzed using Western blots in 84 primary ovarian cancers and seven cell lines of known p53 mutation status. Expression of p16 and Rb also was determined using immunohistochemistry and the p16 gene was examined for homozygous deletions and mutations.Results. Loss of p16 protein was more frequent in ovarian cancers with wild-type p53. All four cell lines with wild-type p53 had lost p16 compared to only one of three with mutant p53 genes. p16 expression was absent in 34% (28/82) of primary ovarian cancers, and this was significantly more common in cases with wild-type p53 (14/28, 50%) compared to those with p53 mutations (14/54, 26%, P = 0.03). Homozygous deletion of the p16 gene was found in cell lines lacking p16, but not in any primary cancers. p16 loss was more common in serous (21/52, 40%) than nonserous cancers (4/23, 17%, P = 0.07). Cases that expressed p16 were more likely to express high levels of Rb (47/55, 85%) than p16-negative cases (12/28, 43%, P < 0.001). Loss of Rb occurred in 5/30 (17%) ovarian cancers lacking p53 mutations compared to 5/54 (9%) cases with p53 mutations (P = 0.48). Expression of G1 stimulatory proteins (cyclins D1 and E, cdk4, Ki67) did not correlate with p53 mutation status.Conclusions. Loss of expression of the p16 tumor suppressor occurs more often in ovarian cancers lacking p53 mutations. These data are consistent with the paradigm that inactivation of p53 is less of a requisite event in ovarian carcinogenesis when another G1 regulatory gene such as p16 already has been inactivated.