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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cause of Li-Fraumeni syndrome, a rare group syndrome of familial cancers, has recently been identified. Patients with this inherited condition are highly susceptible to specific neoplasms, including early-onset breast cancers. The available evidence links Li-Fraumeni syndrome to inherited mutations of the tumor suppressor gene p53. Moreover, somatically acquired p53 mutations and gene deletions are common feature in breast cancer of sporadic origin. These findings suggest that germline p53 mutations are important in familial and, possibly sporadic, breast tumors. We have therefore screened lymphocyte DNA from 19 unrelated bilateral cancer patients for germline p53 mutations in exons 5, 6, 7 and 8. We have however detected no germline mutations by means of the single-strand confirmation polymorphism technique in any of the lymphocyte DNAs examined and conclude that p53 mutations are not generally involved in bilateral breast cancer.
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PMID:Absence of p53 germ-line mutations in bilateral breast cancer patients. 158 36

In the past year we have witnessed significant progress in understanding the molecular basis of cancerogenesis and in identifying the genetic determinants of susceptibility to cancer. In particular, the finding that the same tumor suppressor genes play a pathogenic role in both the inherited and the sporadic forms of some childhood tumors has suggested that this gene class may also be involved in adult tumors derived from inherited familial cancer syndromes. The identification of the gene defect underlying the Li-Fraumeni syndrome, a germline mutation of the tumor suppressor gene p53, has fully confirmed that suggestion. Three other genes associated with the inherited cancer syndromes neurofibromatosis type I (NF-1) and familial adenomatous polyposis have been cloned and partially characterized. In addition to these genes, which have a relatively high penetrance and contribute directly to tumorigenesis, other genes that lead to cancer as a secondary effect seem to act in determining an individual's overall cancer risk. The latter genes are most likely related to defective processes of DNA repair or to regulation of carcinogen metabolism. In this context the analysis of models of murine strains with different genetic susceptibility to cancer of various organs may be a useful tool for unveiling the genetic basis for cancer susceptibility in individuals.
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PMID:Genetics and cancer. 159 Dec 84

The constant denaturant gel electrophoresis technique was used to screen for TP53 germ line mutations in 237 women with breast carcinoma (167 unselected patients, 30 patients with at least one first-degree relative with breast cancer, and 40 women diagnosed with breast cancer before age 35). A germ line mutation at codon 181 was noted in one of the unselected patients and a codon 245 mutation in one of the early-onset patients. Both had a family history of breast cancer and other malignancies suggestive of Li-Fraumeni syndrome. The codon 245 mutation was also present in this patient's affected mother.
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PMID:Screening for germ line TP53 mutations in breast cancer patients. 159 32

Genetic analyses of unusual hereditary cancers and of common neoplasms suggest that tumorigenesis proceeds through a series of genetic alterations involving oncogenes and tumor-suppressor genes. Such genes can be viewed as tumor-susceptibility genes, and DNA tests that examine them might be useful in determining an increased risk of cancer development before the onset of a tumor. Indeed, DNA tests have already proved useful in the genetic counseling of families with an increased risk of rare inherited diseases such as retinoblastoma, multiple endocrine neoplasia type 2a, or Li-Fraumeni syndrome. The current investigation of these familial disorders is enabling the development of expertise, reagents, and methods that will eventually focus on the most common cancers. In assessing risk for these common tumors, several genes will probably require study to achieve more accurate prediction of cancer risk. For example, genetic abnormalities of the ras oncogene and of either the retinoblastoma gene (Rb) or the p53 tumor-suppressor gene have been found in many tumors and appear to be particularly important in the study of individuals at increased risk of lung, breast, or colon cancers. In addition, the study of tumor-associated markers that might already be detectable in the preneoplastic state can be carried out in parallel with tests that search for evidence of mutations in tumor-susceptibility genes. Finally, both classes of markers might be complementary in genetic counseling or screening of populations at increased risk. However, the capacity for detecting tumor-susceptibility markers creates a responsibility for the physician in terms of the proper use of this information.
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PMID:Tumor-susceptibility markers. 161 94

Hereditary breast cancer is common and accounts for approximately 10-14% of all breast cancers. Knowledge of a family history of breast cancer may significantly influence diagnosis and therapy. Genetic heterogeneity has been demonstrated in familial breast cancer. Recently inherited mutations in the tumor suppressor gene p53, have been shown to be the underlying defect in the Li-Fraumeni syndrome. We have shown that defects in this gene also play a role in the predisposition to other familial breast cancers. The gene responsible for early onset familial breast and ovary cancer has recently been mapped to chromosome 17q21. For most of the sporadic breast cancers a multifactorial model, including variable genetic and environmental factors, has been considered. Two genetic risk factors which may predispose for a considerable portion of breast cancers are the gene causing ataxia telangiectasia (AT) and the gene that gives rise to proliferative breast disease (PBD). Identification of distinct genes enhancing the risk of breast cancer will give us the opportunity to identify high risk individuals. Such individuals may benefit from periodic examination affording the possibility of early diagnosis and treatment.
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PMID:Role of genetic factors in breast cancer susceptibility. 162 29

Germ-line mutations in the p53 tumor suppressor gene have been observed in patients with Li-Fraumeni syndrome, brain tumors, second malignancies, and breast cancers. It is unclear whether all of these mutations have inactivated p53 and thereby provide an increased risk for cancer. Therefore, it is necessary to establish the biological significance of these germ-line mutations by the functional and structural analysis of the resulting mutant p53 proteins. We analyzed the ability of seven germ-line mutant proteins observed in patients with Li-Fraumeni syndrome, second primary neoplasms, or familial breast cancer to block the growth of malignant cells and compared the structural properties of the mutant proteins to that of the wild-type protein. Six of seven missense mutations disrupted the growth inhibitory properties and structure of the wild-type protein. One germ-line mutation retained the features of the wild-type p53. Genetic analysis of the breast cancer family in which this mutation was observed indicated that this germ-line mutation was not associated with the development of cancer. These results demonstrate that germ-line p53 mutations observed in patients with Li-Fraumeni syndrome and with second malignancies have inactivated the p53 tumor suppressor gene. The inability of the germ-line p53 mutants to block the growth of malignant cells can explain why patients with these germ-line mutations have an increased risk for cancer. The observation of a functionally silent germ-line mutation indicates that, before associating a germ-line tumor suppressor gene mutation with cancer risk, it is prudent to consider its functional significance.
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PMID:Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. 163 Nov 37

Germline p53 mutations have been identified in the Li-Fraumeni syndrome but the role of such mutations in familial leukemia is not established. The p53 gene was examined by single-strand conformation polymorphism analysis of exons 4-8 in 10 families with multiple members affected with leukemia. The diagnoses included acute and chronic leukemias and Hodgkin's disease. Identified in two families were p53 mutations that were nonhereditary. These included a 2-bp deletion in exon 6 found in the lymphoblast DNA of one child whose sibling, cousin, and several adult relatives had acute leukemia. The other nonhereditary p53 mutation was a transition at codon 248 (CGG to CAG, arginine to glutamine) found in the lymphoblasts of a patient with a preleukemic syndrome and acute lymphoblastic leukemia (ALL) whose brother is a long-term survivor of ALL. Thus, p53 mutations were found to occur in two families but both were nonhereditary. Moreover, in the remaining eight families no p53 mutation was identified in the regions of p53 where most mutations have been found in other cancers. Although p53 mutations sometimes may be present, they do not appear to be a primary event responsible for hereditary susceptibility to familial leukemia. This study suggests involvement of other genes or mechanisms.
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PMID:Absence of hereditary p53 mutations in 10 familial leukemia pedigrees. 164 30

Germline mutations within a defined region of the p53 gene have recently been found in families with the Li-Fraumeni syndrome (LFS). In the present study this region of p53 was sequenced in affected individuals from 8 families with LFS. In only 2 of them were such mutations detected. Our findings suggest that the p53 mutation could be the primary lesion in some but not all families with LFS, and confirm that there is a "hot spot" for these mutations at the CpG dinucleotide moiety of codon 248. Assigning risks and counselling families on the basis of presence of p53 mutations should be approached with caution.
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PMID:p53 germline mutations in Li-Fraumeni syndrome. 168 21

The p53 gene was examined in primary lymphoblasts of 25 pediatric patients with acute lymphoblastic leukemia by the RNase protection assay and by single strand conformation polymorphism analysis in 23 of 25 cases. p53 mutations were found to occur, but at a low frequency (4 of 25). While all four mutations were identified by single strand conformation polymorphism, the comparative sensitivity of RNase protection was 50% (2 of 4). Heterozygosity was retained at mutated codons in 3 of 4 cases. One pedigree was consistent with the Li-Fraumeni syndrome, and bone marrow from both diagnosis and remission indicated a germline G to T transversion at codon 272 (valine to leucine). Although members of another family were affected with leukemia, a 2-bp deletion in exon 6 was nonhereditary. The other two nonhereditary p53 mutations included a T to G transversion at codon 270 (phenylalanine to cysteine) and a G to C transversion at codon 248 (arginine to proline). These data support the role of both hereditary and acquired p53 mutations in the pathogenesis and/or progression of some cases of childhood acute lymphoblastic leukemia.
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PMID:Hereditary and acquired p53 gene mutations in childhood acute lymphoblastic leukemia. 173 52

Tumors derived from a Li-Fraumeni syndrome cancer-susceptible family were examined for expression of the retinoblastoma susceptibility gene (RB). Whereas RB expression was normal in a primary breast carcinoma and its metastases from one member of this family, overexpression of RB was found in an adrenocortical carcinoma from another family member. This was in contrast to normal RB expression in normal tissue of this patient, the adrenocortical adenocarcinoma cell line SW-13, and the fibroblast cell line MRC-5, and low level RB expression in normal adrenal tissue. The overexpression in the adrenocortical carcinoma resulted in increased synthesis of the RB-encoded protein and did not appear to be associated with RB amplification or rearrangement. This result is novel as it is usually the loss of expression or production of an altered RB transcript exhibiting deletions that is associated with carcinogenesis. In light of the recent discovery of p53 point mutations in the affected Li-Fraumeni syndrome family members tested, RB overexpression may constitute a secondary event in Li-Fraumeni syndrome tumorigenesis.
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PMID:Overexpression of the retinoblastoma gene in a familial adrenocortical carcinoma. 175 10


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