Mutation of the nm23 gene, loss of heterozygosity at the nm23 locus and K-ras mutation in ovarian carcinoma: correlation with tumour progression and nm23 gene expression.

Alteration of expression levels of the nm23 genes has previously been correlated with metastatic status of ovarian epithelial carcinoma. To elucidate the relevance of the qualitative changes of the nm23 genes to progression of ovarian carcinoma and/or to nm23 expression levels of the tumour, 41 samples of epithelial ovarian tumours [three benign, three low malignant potential (LMP), and 35 frankly malignant tumours] were studied for mutation of the nm23-H1 and the nm23-H2 genes using single-strand conformational polymorphism (SSCP) analysis. In addition, loss of heterozygosity (LOH) at the nm23 locus on chromosome 17q was studied by CA repeat polymorphism analysis. Mutation of the K-ras gene was also analysed in the same specimens. A novel mutation of the nm23 gene was found in one case of stage III serous carcinoma without lymph model metastases. Sequencing of the subcloned mutant cDNA revealed a missense mutation from TGG to CGG at codon 133 of the nm23-H2 gene, resulting in a change from Trp to Arg. LOH at the nm23 locus was detected in 5 of 23 (21.7%) informative cases of ovarian carcinoma. Mutation of the K-ras gene was detected in 2 of 35 (5.7%) carcinomas at codons 12 and 13 respectively. There was no correlation between clinical stage or metastatic status of ovarian carcinoma and nm23 mutation, LOH at the nm23 locus or K-ras mutation. The expression levels of both the nm23-H1 and the nm23-H2 genes were lower in the tumour with nm23-H2 mutation and higher in those with K-ras mutation. This suggests that mutation of the nm23 genes and the K-ras gene affects carcinogenesis or progression of ovarian carcinoma by modulating expression of the nm23 genes.