The association of a germ-line p53 mutation with an intracranial malignancy and a strong family history of cancer suggests that p53 gene mutations predispose a person to malignancy and, like retinoblastoma mutations, may be inherited.
A new technique for characterizing somatic mutations in very small samples of cellularly heterogeneous human cancer tissue was developed and tested using mutations in the p53 gene in breast carcinomas as a model system.
One major goal of studying the status of p53 (and other tumor suppressor genes) in human cancer is to facilitate the suppression of the tumorigenic phenotype through the restoration of the expression of the wild-type allele.
We have discovered three mutants of human p53 that are temperature sensitive for conformation; one is mutated at codon 273, a 'hotspot' for p53 mutation in human cancer.
Overexpression of the nuclear phosphoprotein p53 is one of the most frequently detected abnormalities in human cancer and appears to be associated with mutation of the p53 gene.
Overexpression of the nuclear phosphoprotein p53 is one of the most common abnormalities in primary human cancer and appears to be due to point mutation within a highly conserved region of the p53 gene which then encodes for a mutant, more stable protein.
Results suggested that aberrations of the p53 gene were not correlated with the malignancy of some types of brain tumors such as anaplastic astrocytoma and glioblastoma, contrary to previous observations on colorectal cancers.
The fact that P53 gene mutations occurred more often in patients with 17p monosomy seems to support the "recessive" model of tumor suppressive activity of the P53 gene rather than the "dominant" model, in which alteration of only one allele is sufficient for the development of malignancy.
In particular, the discovery of tumor suppressor gene syndromes, such as Rb1 gene and p53 gene defects manifested in "cancer families," were made possible by their association with sarcomas, otherwise rare tumors.
These findings represent one of the highest incidences of this oncogenic mutation yet recorded in a human malignancy and support the concept that p53 may have a functional role in development of the metastatic tumor phenotype.
Its location extends the region of the p53 gene where inherited mutations predisposing to cancer are observed and suggests that their distribution may be diverse.
The nuclear protein p53 has been reported to be associated with cell transformation and/or proliferation so that the study of p53 expression in human malignancy has potentially important clinical implications.
These observations provide strong support for the inclusion of the p53 locus in the group of loci whose functional inactivation by either dominant or recessive modes plays a significant role in human cancer.
Mutations of the p53 tumor-suppressor gene, as determined by the immunohistochemistry of archival formalin-fixed specimens, have been correlated with the prognosis for patients with many different types of malignancy.
Thyroid cells carrying a mutated p53 gene did not form colonies in soft agar or tumors in athymic mice, suggesting that a mutation of the p53 gene is not sufficient for the induction of the malignant phenotype and probably a cooperation with other oncogenes is necessary to accomplish full malignancy.
Surprisingly, given the proposed role for loss of function mutations of the p53 gene in the development of human colorectal cancer, we have found no evidence for either an increase in the rate of adenoma formation in APC +/-, p53 -/- animals, or an increased rate of progression to malignancy compared with APC +/- p53 +/+ mice.
With use of this approach, gross alterations in the p53 locus were demonstrated in benign cells in 1 of 20 (5%) specimens harboring high-grade malignancy (Gleason grade 7 or higher).
Among the 65 cases, p53 and hsp70 immunoreaction in cancer cell nuclei was detected immunohistochemically in 16 (25%) and 23 (35%) cases, respectively.