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

A small proportion of breast cancer (perhaps about 5%) and a higher proportion of early onset cases are due to the inheritance of mutations in dominant susceptibility genes which confer a high lifetime risk of the disease. This would equate to about 1250 cases per year in the U.K. and 9000 in the U.S.A. Even within these cases, there is genetic heterogeneity, i.e. there are several genes involved, each giving rise to different patterns of other cancers associated with the familial breast cancer. One such gene (p53) has been identified and a second (BRCA1) has been precisely mapped in the human genome, but further breast cancer predisposition genes remain to be identified. In addition, there are other genes which confer a lower risk of the disease, but may account for a larger proportion of cases, the most important example to date being ataxia telangiectasia. The identification of these genes will enable the entity of familial breast cancer to be more precisely defined and has implications for management of gene carriers with breast cancer and their relatives who are at risk. A major consideration in this new area of cancer genetics is that the identification of gene carriers may become possible on a large scale and this raises ethical and social issues.
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PMID:The genetics of familial breast cancer and their practical implications. 799 29

Perturbations of oncogenes in breast carcinoma include amplifications of the HER-2/neu and PRAD1 genes, as well as p53 mutations. Some of these lesions frequently appear in early cancers such as ductal carcinoma in situ and are stable as the tumors become invasive and metastasize. Thus these findings suggest that oncogene mutations may define a point of origin for a given breast cancer, and are fixed lesions during tumor progression. Such germline abnormalities may occur at the BRCA1, H-RAS VNTR, and p53 loci. The rational use of genetics may be to identify women at high risk for the development of breast cancer so that they may be enrolled in future chemoprevention trials.
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PMID:Oncogenes, breast cancer, and chemoprevention. 800 94

Four genes are now known to be responsible for inherited susceptibility to breast cancer: the BRCA1 gene on chromosome 17q21, the ataxia-telangiectasia (AT) gene (11q22-q23), the TP53 gene (17p13.1) and the androgen receptor (AR) (Xq11.2-q12). These genes, however, differ dramatically in terms of the risk of breast cancer that they confer, the proportion of breast cancer incidence that they account for and the other cancers and other phenotypes with which they are associated. Genetic linkage studies have shown that some high risk breast cancer families, particularly those where breast cancer occurs in association with ovarian cancer, are due to a gene on chromosome 17q known as BRCA1. The BRCA1 gene is estimated to confer a breast cancer risk of about 70% by age 70, and may account for about 2% of overall breast cancer incidence, although a higher proportion of younger cases. Germline mutations in the TP53 gene are responsible for a high proportion of LI-Fraumeni families, in which breast cancer occurs in association with childhood sarcomas and other cancers. In such families, the risk of breast cancer is over 50% by age 50, and the risk of all cancers is nearly 100%; germline TP53 mutations are, however, probably responsible for much less than 1% of all breast cancer. By contrast, heterozygotes for the AT gene carry a much more moderate risk of breast cancer. This gene, however, is much more common in the population and may account for 7% or more of breast cancer incidence. Finally, germline mutations in the androgen receptor are known to cause male breast cancer, but this has only been demonstrated in two families. Evidence from linkage and population based studies suggests that these genes may account for about one half of the observed familial clustering of breast cancer; other breast cancer susceptibility genes therefore remain to be identified.
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PMID:Inherited susceptibility to breast cancer. 801 3

The isolation of genes that predispose to familial disease is an important goal in cancer research. The identification of such genes "opens up" the possibility of genetic diagnosis in families so that individuals who are at risk of cancer through inheriting a predisposing mutation can be identified. Genes that are involved in familial cancer syndromes may also be important in the pathogenesis of sporadic forms of the disease, which are often more common. In the search for genes that predispose to familial breast and ovarian cancer much recent progress has been made. A locus on the long arm of chromosome 17, in the interval 17q12-21, has been identified by genetic linkage, and appears to be responsible for disease in approximately 40% of breast cancer families and most families that contain breast and ovarian cancer. The region containing this locus, which has been called BRCA1, has been narrowed to a 3-4 cM interval defined by THRA1, the thyroid hormone receptor locus alpha, and D17S183, an anonymous microsatellite polymorphism. Loci other than BRCA1 that have been identified appear not only to predispose to breast and/or ovarian tumors, but to tumors at other sites too. A new locus has been identified on chromosome 2 which is linked to hereditary non-polyposis colorectal cancer (HNPCC). Families with HNPCC are also at risk of endometrial cancer and tumors of the ovary, amongst other cancer sites. Finally, mutations in the p53 gene are inherited in families with Li-Fraumeni syndrome, a rare cancer syndrome predisposing to breast tumors, sarcomas, leukemia and other cancers. Li-Fraumeni syndrome is also the only inherited cancer syndrome that predisposes at least in part to breast cancer where the actual predisposing gene is known. For the other cancer syndromes, the cloning of the predisposing genes is eagerly awaited.
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PMID:Predisposing genes in breast and ovarian cancer: an overview. 811 68

Germline mutations within evolutionary conserved exons of the p53 gene predispose to tumor development in several familial cancer syndromes. We now report identification of a novel p53 mutation affecting the splice acceptor site of exon 6 in the germline DNA of a family with hereditary breast-ovarian cancer. This splice-site mutation, which results in omission of exon 6 and creates a frame-shift and premature stop codon in transcripts from the mutant allele, was found in seven family members--four of whom have developed breast, ovarian or choroid plexus tumors before age 35. Our finding suggests the need to examine the entire p53 gene for splice-site, frame-shift, and nonsense (as well as missense) mutations in families with early-onset hereditary breast and breast-ovarian cancers not linked to the BRCA1 gene on chromosome 17q. We propose that the term 'p53 familial cancer syndrome' be applied to clusters of tumors in families with documented germline p53 mutations, regardless of the histopathologic findings or pattern of tumor development.
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PMID:Splice-site mutation of the p53 gene in a family with hereditary breast-ovarian cancer. 830 8

Three loci have been implicated in the etiology of familial breast cancer; the BRCA1 locus on 17q, the p53 gene on 17p, and the androgen receptor gene on the X chromosome. However, it has been estimated that in approximately 50% of all breast cancer families the predisposing genetic defect is not linked to any of these three loci. In an attempt to identify chromosomal regions harboring putative breast cancer genes we performed allelotyping in 82 familial breast carcinomas. Polymorphic markers representing 45 different loci were analyzed and the most frequently involved chromosomal arms were 8p, 16q, 17p, 17q, and 19p.
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PMID:Loss of heterozygosity in familial breast carcinomas. 836 30

Two genes predisposing females to autosomal dominant breast cancer are located on chromosome 17. Mutations in the p53-gene on the short arm have been shown to predispose females to early onset breast cancer in families with the rare Li-Fraumeni syndrome. Another locus on 17q (BRCA1), was found to be linked to the disease in a subset of families with breast cancer. In order to determine the involvement of tumour suppressor genes at these loci in tumour development, we studied allele losses for markers on chromosome 17 in 78 familial breast carcinomas. The analysis used six polymorphic DNA markers, three on each arm. We found support for at least four separate regions displaying allele losses on chromosome 17: the p53-region, the distal part of 17p, the BRCA1 region and the distal part of 17q. The frequency of allele losses on distal 17p (16%) is low in these familial tumours compared with the previously reported incidence in sporadic tumours (> 50%), whereas the frequency of losses at the p53 locus and on 17q was similar to sporadic tumours (5%-40%). These data suggest that several regions on chromosomal 17 can harbour tumour suppressor genes involved in tumour development of familial breast cancer.
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PMID:Four separate regions on chromosome 17 show loss of heterozygosity in familial breast carcinomas. 845 89

Japanese breast cancer families were collected and classified into the following 7 types according to the onset age and the distribution of other cancers in the family lines; early-onset type, late-onset type, familial breast-ovarian cancer type, familial breast-prostate cancer type, familial breast-thyroid cancer type, familial male and female breast cancer type and multiple primary cancer type. We have detected no p53 germ line mutations in the patients from these families. Linkage with BRCA1 was not detected in any single families. These data indicate that neither BRCA1 or p53 is a major susceptible gene in Japanese familial breast cancer. However, in the two site-specific breast cancer families, the same nonsense mutation of the BRCA1 gene was detected.
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PMID:[Familial breast cancer]. 853 41

An estimated 5 to 10% of all breast and ovarian cancer is attributable to inherited mutations in two highly penetrant autosomal dominant susceptibility genes, BRCA1 and BRCA2. BRCA1 confers higher risk of ovarian cancer and BRCA2 much higher risk of male breast cancer. With the exception of missense mutations in the RING finger near the amino terminus of BRCA1, virtually all germline mutations in the gene cause the novel BRCA1 protein to be prematurely truncated. Approximately 90% of breast tumors in BRCA1 families, 50% of unselected breast tumors and 65-80% of unselected ovarian tumors have lost one allele of BRCA1 by somatic deletion. Very few tumors have detectable somatic point mutations in BRCA1. Inhibition of BRCA1 expression in mammary epithelial cell lines also suggests that BRCA1 may act as a tumor suppressor. The biological function of BRCA1 is still unknown, although identification of a patient homozygous for an inherited BRCA1 mutation suggests that the gene's function may be essential only to specific tissues. At least two other genes, P53 and the androgen receptor, are responsible for inherited predisposition to breast cancer in rare families. Several epidemiologic studies suggest that individuals carrying rare alleles at a minisatellite flanking the HRAS locus are at increased risk of cancer, including breast cancer. Finally, preliminary epidemiologic studies also suggest that individuals heterozygous for mutations in the ataxia telangiectasia gene may be at increased risk of breast cancer.
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PMID:Inherited breast and ovarian cancer. 854 81

Multiple chromosome 17 loci may be involved in ovarian carcinogenesis. Fifty-seven sporadic ovarian epithelial tumors were examined for loss of heterozygosity at 15 loci on chromosomes 17p. Eighty % (39 of 49) of informative tumors had allelic loss in 17p13.3 at D17S30, D17S28, or both loci within this region, including 3 of 7 tumors of low malignant potential and 4 of 5 nonmetastatic carcinomas. The smallest region of overlapping deletions extends from D17S28 to D17S30, a distance of 15 kb. Furthermore, several tumors have breakpoints within the region detected by the D17S30 probe. Chromosome 17p13.3 genes with potential tumor suppressor function include HIC-1, DPH2L (N. J. Phillips et al. Isolation of a human diphthamide biosynthesis gene on chromosome 17p13.3, submitted for publication)/OVCA1, PEDF, and CRK. The HIC-1 coding sequence lies i kb centromeric to the D17S28-S17S30 region of deletion (M. Makos Wales et al., Nat. Med., 1:570-577, 1995) but remains a candidate because 5'-regulatory elements may lie within the critical region. Portions of the DPH2L/OVCA1 coding sequence lie within the D17S28-D17S30 interval. Somatic cell hybrid analysis places PEDF in an interval including D17S28, D17S30, and D17S54, whereas CRK is excluded from this interval. Chromosome 17p13.3 loss precedes TP53 and BRCA1 region deletions because the latter changes are see only in high-stage carcinomas. Microsatellite instability plays only a minor role in sporadic ovarian carcinogenesis because only 1 of 57 tumors showed this finding.
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PMID:Allelic deletion on chromosome 17p13.3 in early ovarian cancer. 856 79


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