The role of tumour suppressor genes in ovarian cancer
The role of tumour suppressor genes, in particular p53 and DCC, was investigated in human ovarian cancer. p53 codes for a DNA-binding nuclear phosphoprotein whose expression, in the wild-type form, is essential in the control of the cell cycle. Loss of function of this gene by mutation allows unrestrained cell proliferation to occur. The function of the DCC gene is not yet fully understood. A total of 29 malignant epithelial ovarian tumours, 15 of borderline malignancy, and 12 benign tumours were collected for study. Allele loss analysis confirmed that deletion of the p53 and DCC genes had occurred in 40&'37 and 41&'37 of the malignant tumours respectively. Two additional regions of loss were also identified at 17p13.3 (63&'37 ) and 17q23-qter (83&'37 ). Using SSCP analysis and direct DNA sequencing of exons 5 to 8, 52&'37 of the malignant tumours studied were found to have a p53 mutation. No mutations were found in any of the borderline or benign tumours. Immunocytochemical analysis of tissue sections from each of the tumours demonstrated that p53 over-expression had occurred in 55&'37 of the malignant tumours studied, and also in one of the borderline tumours. In total, 66&'37 of the malignant tumours were shown to have a p53 abnormality with either a mutation and/or protein over-expression. No correlation was found between any of the molecular abnormalities and either FIGO stage, the histopathological type of tumour, or the degree of tumour cell differentiation. However, a strong correlation was found between DCC allele loss and p53 mutation, and five out of six of the women whose tumours had both of these abnormalities died between 10 and 48 months after initial diagnosis. Finally, linkage analysis was carried out on a large breast/ovarian cancer family and it was confirmed that neither a mutation in the p53 gene nor a mutation in the DCC gene were responsible for the inherited predisposition to cancer.