In this study we examined 63 methylcholanthrene (MCA)-induced sarcomas from C57BL/6N x C3H/HeN F1 (BCF1) or C3H/HeN x C57BL/6N F1 (CBF1) mice for p53 gene mutations and loss of heterozygosity (LOH) of chromosome 11.
Compared with other highly malignant mesenchymal pediatric tumors such as osteosarcomas, mutations of p53 and ras in Ewing's sarcomas are an extraordinarily rare event.
The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.
We examined the effect of overexpression of p21(waf1) on cytotoxicity of paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma protein and p53.
A high proliferative index was demonstrated in 27.5% (11/40) of the tumours (2 MFH, 4 leiomyosarcomas, 1 rhabdomyosarcoma, 1 osteosarcoma, 2 Ewing's sarcomas and 1 unclassified sarcoma). p53 overexpression was associated with high tumour grade (p < 0.05) and MIB-1 expression was correlated with reduced survival (p < 0.05), but p53 overexpression was not significantly associated with either MIB-1 score or with overall survival of the patients.
To determine the role of p53 in G2/M arrest, G2/M transition and apoptosis, we investigated five human sarcoma cell lines with different p53 gene status in their response to X-rays.
Because these rare tumors also respond poorly to standard chemotherapy and bear a 50% 5-year mortality rate, we investigated the possible therapeutic benefits of p53 gene restoration in sarcomas.
The different incidence of TP53 abnormalities in the 2 types of sarcoma may reflect differences of the molecular processes through which the 2 types of tumor develop.
These results suggest that p53 abnormality occurs during advanced stages of sarcoma and are related to patient prognosis, and it is possible that aberrations in mismatch repair activity are related to sarcoma tumorigenesis.
We also analyzed P53 status, because this parameter has been found to have a significant prognostic impact in other sarcomas with chromosomal translocations.
The results support the hypothesis that the prevention of irradiation induced G2/M arrest but not the induction of apoptosis plays a critical role in determining radiosensitivity in sarcoma cell lines with p53 mutations.
Germline mutations of the p53 coding region are present in approximately 50-70% of patients with Li-Fraumeni Syndrome (LFS), a rare hereditary disorder of familial and intraindividual clustering of different malignancies such as sarcoma (index tumor), breast cancer, brain tumors, leukemias, and adrenocortical carcinomas, the latter usually in young children.