The pathogenetic significance of p53 and c-Ki-ras gene mutations and genomic integration of human papillomavirus (HPV) DNA was examined in surgically resected specimens of adenocarcinomas of the uterine cervix and isthmus using polymerase chain reaction (PCR), single-strand-conformation polymorphism and Southern blotting analysis. Among 25 cervical adenocarcinomas, p53 gene mutations between exons 5 and 8 were detected in 32%, and the incidence of these mutations was higher in cases at advanced clinical stages and with high grades of nuclear and structural atypia both in endocervical and in endometrioid types. HPV DNA type 16 or 18 in cervical adenocarcinomas was detected in 35% of cases by PCR and in 29% by Southern blotting, and, in contrast to the p53 mutations, the majority of cases with the HPV DNA were at a relatively early clinical stage with low-grade histological atypia. c-Ki-ras gene mutation was detected in only 4% of cervical adenocarcinomas. Among 8 isthmus adenocarcinomas, the incidence of p53 and c-Ki-ras gene mutations, and the presence and integration of HPV DNA type 16 or 18 were 38%, 50%, 57% and 25% respectively. The pattern of p53 mutations differed between isthmus and cervical adenocarcinomas: all of the mutations in the former were one-base substitutions of the transition type, whereas in the latter nearly half of the mutations were of the transversion type. Among cervical adenocarcinomas, p53 mutations between exons 5 and 8 were indicated as being mostly involved in the pathogenesis and development of biologically aggressive tumors, whereas HPV type 16 or 18 infection appeared to be involved in less aggressive cases. In isthmus adenocarcinoma, c-Ki-ras gene mutation, apart from p53 mutation and HPV-type-16 or -18 infection, appeared to be involved frequently in cancer development.

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Adenocarcinoma of the uterine cervix (CxAd) is one of the most distressing malignancies of the female reproductive system because of its tendency to spread aggressively and to be resistant to radiation and systemic therapies. To clarify the prognostic significance of p53 alteration in CxAd, we immunohistochemically examined the incidence of p53 nuclear accumulation, which is considered to be mostly parallel with p53 gene mutation, and its association with clinicopathological parameters in 26 patients with CxAd. The overall incidence of p53 nuclear accumulation was 46% (12 of 26), being higher in groups with clinically advanced disease, higher degrees of cellular atypia, and deeper myometrial invasion, but significantly lower in patients with integration of human papillomavirus (HPV) type 16 or 18 DNA. Nuclear p53 immunoreactivity as well as lymph node status, depth of invasion and the absence of HPV‐DNA integration were significant indicators of a poor prognosis. Examination of p53 nuclear accumulation could be applied to biopsy material, and would be of practical assistance in predicting the prognosis of CxAd both preoperatively and postoperatively.

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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