On the other hand, p53 is a well-characterized tumor suppressor gene and p53 heterozygous mice develop sarcoma and other tumors starting from 12 months of age.
Abnormalities identified by immunohistochemistry included p21 immunonegativity (60%, 25%, 93%), which was most frequent in TE-GBM (P = .008), strong nuclear p53 staining (29%, 29%, 41%), strong membranous staining for epidermal growth factor receptor (EGFR) (21%, 63%, 19%), which was most frequent in E-GBM (P = .03), and an increased frequency of p27 immunonegativity in gliosarcomas (15% negative, 85% focal) compared with tumors without sarcoma (38% strongly positive) (P = .009).
A tumorigenic connection between the oncogene product Mdm2 and tumor suppressor p53 is generally accepted, but their possible clinical relevance has not yet been investigated sufficiently in soft tissue sarcoma.
Molecular assessment of clonality leads to the identification of a new germ line TP53 mutation associated with malignant cystosarcoma phyllodes and soft tissue sarcoma.
The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas.
The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines.
Mutation of the p53 tumor suppressor gene, with resultant overexpression of p53 protein, frequently occurs in human soft tissue sarcomas, supporting the role of p53 mutations in the pathogenesis of soft tissue sarcoma and the possible usefulness of p53 immunolocalization as a screening method for p53 mutations.
APC mutated (Min) mice develop large and small bowel adenomas, a small proportion of which, in time, become malignant. p53 deficient mice develop predominantly lymphoma and sarcoma.
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 propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists.
Germline alterations of the tumour suppressor TP53 gene are detected approximately in 25% of the families suggestive of Li-Fraumeni syndrome (LFS), characterised by a genetic predisposition to a wide tumour spectrum, including soft-tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumours, adrenocortical tumours, plexus choroid tumours, leukaemia and lung cancer.
These results demonstrated the dominance of the p53 mutations with null protein expression in bone and soft tissue sarcomas, showing a unique characteristic of these types of tumours compared with other malignancies such as colon carcinomas.
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.
In this study, we assess the apparent generation effect on cancer incidence in ten extended families with P53 germline mutation, identified through probands diagnosed with childhood sarcoma.