The Donryu rat has been found to have a high incidence of spontaneous uterine endometrial carcinomas. Moreover the histologic findings, biological nature and pathogenesis of these rat tumors appear similar to those in humans. To determine if the incidence of H- and K-ras gene mutations in these rat tumors is similar to that in human endometrial cancers, we isolated DNA samples from 2 atypical hyperplasias, 5 simple or complex hyperplasia without atypia, 9 adenocarcinomas and 7 histologically normal tissues, amplified exons 1 and 2 of the H- and K-ras genes by PCR and hybridized the products with allele specific oligonucleotide probes. K-ras point mutations were observed in 1/2 of the atypical hyperplasia (codon 12: GGT-->GTT) and 3/9 of the carcinoma (codon 12: GGT-->GAT, GGT-->AGT, codon 61: CAA-->CAC), while they were not detected in 7 of the normal tissues and in 5 of the simple or complex hyperplasia without atypia. H-ras point mutations were not detected in any of these DNA samples. These frequencies in this rat model are similar to those in humans. The absence of K-ras mutations from simple and complex hyperplasia tissue samples suggests that these mutations are associated with cytological atypia. Our findings suggest that alterations in the K-ras gene may be one of the important initiating event in endometrial carcinogenesis in some of the Donryu rat, like the human.

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Samples of abnormal endometrium, which were composed of 5 cases of atypical hyperplasia (ATH), 12 cases of well differentiated adenocarcinoma (G1), 17 cases of moderately differentiated adenocarcinoma (G2), 11 cases of poorly differentiated adenocarcinoma (G3) and 2 cases of serous papillary adenocarcinoma (SPA), were analyzed by flow cytometry. With respect to the ploidy level, all cases of both ATH and G1 showed diploidy, and the proliferative index (PI) was 14.32 and 16.33, respectively. In contrast, 3 of G2 cases, 3 of G3 cases and all of SPA cases showed aneuploid patterns, and the PI was 21.06, 27.91 and 31.52, respectively. There were statistical differences between the former group and the latter group as to both the ploidy and the PI. It was found that ATH and G1 had similar biological behavior.

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