PREDOMINANT P53 G-]A TRANSITION MUTATION AND ENHANCED CELL-PROLIFERATION IN UTERINE SARCOMAS OF CBA MICE TREATED WITH 1,2-DIMETHYLHYDRAZINE

Mouse uterine tumors were examined for genetic alterations in the ras proto-oncogene and p53 tumor suppressor gene and for other biologicall y relevant immunohistochemical markers that may increase our understan ding of the events that occur in uterine cancer. Fourteen dimethylhydr azine (DMH)-induced uterine sarcomas, including 3 primary malignant fi brous histiocytomas (MFH), 7 transplanted MFH, 3 stromal sarcomas, and 1 undifferentiated sarcoma, were first screened by immunohistochemist ry for p53 missense mutations, followed by single strand conformation polymorphism analysis and DNA sequencing for the identification of poi nt mutations. There was 100% correlation between p53 protein immunopos itivity and subsequent detection of p53 mutations in DMH-induced malig nant fibrous histiocytomas. All MFH had a characteristic p53 G:C-->A:T transition mutation, consistent with O-6-methylguanine mispairing wit h thymine, the most common DNA lesion caused by alkylating agents. DMH -induced uterine MFH with p53 mutations also had a higher proliferativ e rate (qualitatively evaluated by immunohistochemical detection of pr oliferating cell nuclear antigen) when compared with other DMH-induced sarcomas. Uterine sarcomas were further evaluated for biological end points, such as estrogen receptor and desmin. Neoplastic cells from st romal sarcomas (SS), undifferentiated sarcomas (US), and MFH did not s tain for desmin. The estrogen receptor was detected in normal uteri an d a small portion of MFH, SS, and US. Our data suggest that DMH-induce d uterine sarcomas are not consistent with smooth muscle cell origin a nd that a subset of these tumors, specifically DMH-induced malignant f ibrous histiocytomas, have unique p53 G:C-->A:T transitions and a high proliferative rate.