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 biologically relevant immunohistochemical markers that may increase our understanding of the events that occur in uterine cancer. Fourteen dimethylhydrazine (DMH)-induced uterine sarcomas, including 3 primary malignant fibrous histiocytomas (MFH), 7 transplanted MFH, 3 stromal sarcomas, and 1 undifferentiated sarcoma, were first screened by immunohistochemistry for p53 missense mutations, followed by single strand conformation polymorphism analysis and DNA sequencing for the identification of point mutations. There was 100% correlation between p53 protein immunopositivity and subsequent detection of p53 mutations in DMH-induced malignant fibrous histiocytomas. All MFH had a characteristic p53 G:C-->A:T transition mutation, consistent with O6-methylguanine mispairing with thymine, the most common DNA lesion caused by alkylating agents. DMH-induced uterine MFH with p53 mutations also had a higher proliferative rate (qualitatively evaluated by immunohistochemical detection of proliferating 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 stromal sarcomas (SS), undifferentiated sarcomas (US), and MFH did not stain for desmin. The estrogen receptor was detected in normal uteri and a small portion of MFH, SS, and US. Our data suggest that DMH-induced uterine sarcomas are not consistent with smooth muscle cell origin and that a subset of these tumors, specifically DMH-induced malignant fibrous histiocytomas, have unique p53 G:C-->A:T transitions and a high proliferative rate.
Trukhanova
L S
LS
Cancer Research Centre, Russian Academy of Medical Sciences, Moscow, Russia.
Hong
H H
HH
Sills
R C
RC
Bowser
A D
AD
Gaul
B
B
Boorman
G A
GA
Turusov
V S
VS
Devereux
T R
TR
Dixon
D
D
D019813:1,2-Dimethylhydrazine; D000818:Animals; D002455:Cell Division; D003893:Desmin / Q000032:analysis; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D008808:Mice, Inbred CBA; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D012513:Sarcoma, Experimental / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014594:Uterine Neoplasms / Q000139:chemically induced / Q000737:chemistry / Q000235:genetics* / Q000473:pathology
D003893:Desmin; D018809:Proliferating Cell Nuclear Antigen; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D019813:1,2-Dimethylhydrazine