HIGH-INCIDENCE OF P53 GENE MUTATION IN HUMAN OVARIAN-CANCER AND ITS ASSOCIATION WITH NUCLEAR ACCUMULATION OF P53 PROTEIN AND TUMOR DNA ANEUPLOIDY

Using the poylmerase chain reaction and single-strand conformation polymorphism analysis, p53 gene mutations were examined in 24 cases of ovarian tumor including 14 ovarian carcinomas and 2 borderline cases of common epithelial type, 7 germ cell tumors, and one stromal tumor. Abnormal bands indicating mutations were detected in 12 (50%) of the cases examined, being present most frequently in common "epithelial" ovarian carcinoma (71%, 10/14). One case each of squamous cell carcinoma originating in a dermoid cyst and anaplastic dysgerminoma were positive for mutation. Direct sequencing confirmed 12 mutations and revealed G-->A and G-->C nucleotide changes in 5 and 3 cases (42% and 25%), respectively. The mutation was localized at the CpG site of the gene in 3 cases. Immunohistochemical examination of p53 protein in 21 cases and DNA flow-cytometrical analysis in 17 cases were also performed. Nuclear accumulation of the p53 protein and DNA aneuploidy pattern were detected in 11 (52%) and 9 (53%) cases, respectively. These were significantly correlated with p53 gene mutation (P<0.01 and P<0.05, respectively; Fisher's exact test). Neither mutation of the p53 gene, nuclear accumulation of p53 protein nor DNA aneuploidy was detected in borderline cases of common "epithelial" type, typical dysgerminoma and immature teratoma. These results suggest that p53 gene mutation, nuclear accumulation of the protein and the DNA aneuploidy pattern are events occurring almost simultaneously in the progression of ovarian tumors, and that p53 abnormalities seem to be correlated with a high grade of malignancy.