Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers?

To investigate the association of DNA mismatch repair deficiencies in the development and/or progression of epithelial ovarian cancers, the relationship between replication errors (RERs) and genetic alterations in three genes (p53, c-erbB2, K-ras) and loss of heterozygosity (LOH) on 6q27 was investigated in 70 patients with epithelial ovarian cancers. The presence of RERs was examined by PCR using five microsatellite markers. Mutations of p53 were analyzed by PCR-SSCP and sequencing. Amplification of c-erbB2 was analyzed by Southern blot hybridization. Point mutations of K-ras codon 12 were identified by PCR-PHFA, while 6q27LOH was examined by Southern blot hybridization. As a result, 18 of 70 patients with epithelial ovarian cancers (26%) were RER-positive and 52 patients (74%) were RER-negative. Tumors with two or three genetic alterations accounted for 28% and 33% of RER-positive tumors, respectively, and these were significantly more frequent than in the RER-negative tumors (17% and 6%, respectively)(P = .002). These results are consistent with mismatch repair deficiencies being involved in the development and/or progression of a proportion of epithelial ovarian cancers through accumulation of genetic alterations.