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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been well established that sometimes cancer clusters within specific families. This has suggested the possibility that some of those families might carry genetic defects which provide susceptibility to specific cancers. Retinoblastoma, an embryonal tumor of the eye represents an extreme example of a tumor which has a dramatic genetic component. Several studies have shown that inactivation at the retinoblastoma gene is probably both necessary and sufficient to initiate retinoblastoma formation. Patients who survive the inherited form of the disease are at risk of developing mesenchymal tumors, melanoma and brain tumors in as high as 10% of the patients before they are 40 years old. Because the product of the retinoblastoma gene, p105Rb, is expressed in all cell types, the obvious question is what accounts for these tissue specific differences in the role of p105Rb. Small cell lung carcinomas virtually all have associated mutations in the Rb gene and yet those tumors do not occur at a significantly increased frequency in patients with the hereditary form of retinoblastoma. In order to identify genes which might predispose to some of the more common adult malignancies, we have focused on one form of hereditary breast cancer. We chose a rare form of hereditary breast cancer which occurs in families with sarcomas (Li-Fraumeni Syndrome). By use of the candidate gene approach we tested which germ line p53 mutations were found in affected family members with Li-Fraumeni Syndrome (LFS). We have found that virtually all of the families with LFS have germ line p53 mutations, and that these tumors have undergone inactivation of the remaining wild-type p53 allele. In order to investigate the role of germ line p53 mutations outside of these rare families, we have begun to investigate other high risk groups. These results indicate that de novo germ line p53 mutations certainly occur in these high risk groups. These findings along with the recognition of the germ line p53 mutations in families with LFS provide clues about the importance of uncovering hidden susceptibilities from germ line tumor suppressor genes not only for the care of patients, but also for understanding the primary events that normally regulate the growth of cells in various tissue.
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PMID:Cancer risks from germ line tumor suppressor gene mutations. 184 52

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. In this study different stages of breast cancer progression were examined, from in situ to metastatic disease, to determine at what stage mutational activation occurs and whether it is maintained during tumor progression. Two (13%) of 15 pure intraductal tumors expressed high levels of p53 in all malignant epithelial cells. Sequencing of p53 mRNA from one of these tumors demonstrated a nucleotide substitution altering the amino acid composition of the protein. Six (17%) of 35 specimens which contained both in situ and invasive disease expressed high levels of p53. All malignant epithelial cells in these 6 cases stained positively and in no specimen did one component express different levels of the protein than the other growth phase. Sequence analysis of a tissue with significant amounts of both in situ and invasive disease revealed only a single point mutation, without evidence of wild-type nucleotide at the site of substitution, suggesting that p53 mRNA from each component of the tumor contained the same nucleotide substitution. Eleven (50%) of 22 pairs of primary tumors and their lymph node metastases expressed elevated levels of p53, and in each case, expression levels were identical in the primary and secondary sites. Identical mutations were found in the p53 mRNA from two paired primary and metastatic sites. Therefore, mutation within a highly conserved region of the p53 gene leading to overexpression of the protein product can occur in the earliest recognized phase of breast cancer and this alteration is maintained during progression from intraductal to infiltrating carcinoma. Mutations are also conserved during the process of metastatic spread.
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PMID:Maintenance of p53 alterations throughout breast cancer progression. 185 Jun 60

The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age, stage, metastatic involvement, concentration of estrogen and progesterone receptors, proliferative index, and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage, metastatic spread, and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.
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PMID:Relation between p53 overexpression and established prognostic factors in breast cancer. 185 36

Mutations in the p53 gene are associated with a wide variety of human tumors, including those of the breast. To assess functionally the role of the p53 gene in the development of human breast cancer, we introduced either wild-type or mutant p53 cDNA into three human breast cancer cell lines by DNA transfection. The cell lines MDA-MB 468 and T47 D contain only single mutated copies of the p53 gene, whereas the status of p53 in the breast cancer cell line MCF 7 remains equivocal. Following transfection, MCF 7 cells continued to grow unaffected both in vitro and in vivo in the presence of high levels of expression of the exogenous wild-type p53 gene. In contrast, however, the continued expression of an exogenous wild-type p53 gene was incompatible with cellular growth in both the MDA-MB 468 and T47 D cell lines. Elevated levels of expression of the exogenous mutant p53 gene did not alter the growth of the cell lines in vitro. These data strongly suggest that the wild-type p53 gene can function as a suppressor of cellular growth in breast cancer cells. That the wild-type p53 gene does not suppress the growth of MCF 7 cells indicates that at least some human breast tumors can arise without functional inactivation of the p53 gene by mutation. These tumors may represent a separate prognostic group.
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PMID:Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. 192 4

This report describes a rare polymorphism at codon 213 (silent alteration of CGA to CGG) within the coding region of the p53 gene. The rare polymorphic allele was present in six cases out of 189 lung and breast cancer DNAs analyzed (3.2%) and resulted in the loss of a TaqI site. This allele could be mistaken for a mutation when screening methods of mutation analysis are used without comparison with normal tissue DNA.
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PMID:Polymorphism at codon 213 within the p53 gene. 192 33

The Li-Fraumeni cancer family syndrome is manifested by susceptibility to breast cancer, sarcomas, and other neoplasms in children and young adults. The present study utilized clinical follow-up data on 545 members of 24 Li-Fraumeni kindreds living and cancer-free at family ascertainment. Two hypotheses were tested based on a model of autosomal dominant genetic predisposition: (a) that syndrome cancers would continue to occur excessively during follow-up compared to the general population, and (b) that the tumors would occur primarily among those family members likely to carry the gene. Population cancer rates were compared with cancer rates in follow-up of the cohort from ascertainment to 1988. Risk of carrying the gene for the syndrome at the time of ascertainment was calculated for each family member under two models with somewhat different definitions of affection with the syndrome. Cancer occurrence after ascertainment was then analyzed according to the risks. Cancer did continue to occur excessively among the entire cohort during follow-up [relative risk (RR 2.1)]. The excess was greatest below age 20 (RR 21.1), declined with increasing age, and was most pronounced for neoplasms featured in the syndrome (RR 18.2). Among persons less than age 45, at least 87% of cancers occurred in those at higher risk of carrying the gene under both genetic models (RR 22.9 and 21.3). The clinical data, therefore, reliably identify individuals likely to carry a dominantly inherited gene conferring susceptibility to a specific constellation of neoplasms. Recent identification of a germ line mutation in the tumor suppressor gene p53 in persons with the syndrome may, if confirmed, have implications for ultimately defining the component tumors of the syndrome and for the causes and prevention of those tumors arising outside these families.
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PMID:Follow-up study of twenty-four families with Li-Fraumeni syndrome. 193 72

Based on the high incidence of loss of heterozygosity for loci on chromosome 17p in the vicinity of the p53 locus in human breast tumors, we investigated the frequency and effects of mutations in the p53 tumor suppressor gene in mammary neoplasia. We examined the p53 gene in 20 breast cancer cell lines and 59 primary breast tumors. Northern blot analysis, immunoprecipitation, and nucleotide sequencing analysis revealed aberrant mRNA expression, over-expression of protein, and point mutations in the p53 gene in 50% of the cell lines tested. A multiplex PCR assay was developed to search for deletions in the p53 genomic locus. Multiplex PCR of genomic DNA showed that up to 36% of primary tumors contained aberrations in the p53 locus. Mutations in exons 5-9 of the p53 gene were found in 10 out of 59 (17%) of the primary tumors studies by single-stranded conformation polymorphism analysis. We conclude that, compared to amplification of HER2/NEU, MYC, or INT2 oncogene loci, p53 gene mutations and deletions are the most frequently observed genetic change in breast cancer related to a single gene. Correlated to disease status, p53 gene mutations could prove to be a valuable marker for diagnosis and/or prognosis of breast neoplasia.
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PMID:Mutations in p53 as potential molecular markers for human breast cancer. 196 33

The DNA of paired tumour and blood leucocyte samples from a large series of breast cancer patients was analysed to map regions of loss of heterozygosity on chromosome 17. The high frequency of loss of heterozygosity on 17p was confirmed, and a third of informative tumours had also lost an allele at the long arm locus THH59. On the short arm two distinct regions of loss of heterozygosity were identified, in bands p13-3 and p13-1. The latter probably involves the structural gene p53, which has been implicated as an oncogene or as a tumour suppressor in various human cancers. 17p 13-3, however, showed a significantly higher frequency of loss of heterozygosity, and there was no correlation between allele losses at the two sites. Nevertheless, loss of heterozygosity at 17p 13-3 is associated with overexpression of p53 mRNA, suggesting the existence of a gene some 20 megabases telomeric of p53 that regulates its expression. Lesions of this regulatory gene seem to be involved in the majority of breast cancers.
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PMID:Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis. 197 43

Allele loss on a specific chromosome has implied the existence of a tumor suppressor gene such as the p53 gene and the RB gene. In order to determine which chromosome(s) carries a tumor suppressor gene(s) that contributes to tumor progression in primary breast cancer, we analyzed the loss of heterozygosity for each autosomal chromosome arm by using 39 restriction fragment length polymorphism markers including 25 variable numbers of tandem repeat probes. In 79 primary breast cancers, we found the frequent loss on the long arm of chromosome 13 (21%), the long arm of chromosome 16 (45%), and the short arm of chromosome 17 (56%). Interestingly, breast cancers in which loss of both chromosomes 13q and 17p was detected showed more malignant histopathological features, and a group of the tumors in which chromosome 16q loss was detected presented with frequent lymph node metastasis. Furthermore, the result of the deletion mapping on chromosome 17p implied the existence of a tumor suppressor gene distal to the p53 gene as well as the p53 gene itself for primary breast cancer. These results suggest that at least 4 tumor suppressor genes exist on chromosomes 13q, 16q, and 17p for primary breast cancer.
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PMID:Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. 197 15

Relatives of 88 long-term survivors of childhood sarcoma were examined for the familial cancer syndrome of sarcoma, breast cancer, and other neoplasms (Li-Fraumeni syndrome). Twenty-six of 402 close relatives developed cancer (expected, 23.8), including breast cancer in four mothers (expected, 3.1). Two sarcoma probands who developed second malignant tumors have multiple relatives with cancer and might have an inherited predisposition. An increased cancer risk and exceptional requirement for disease screening appear to be confined to first-degree relatives of a small fraction of children with sarcoma, notably probands with second cancers.
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PMID:Cancer in relatives of survivors of childhood sarcoma. 199 15


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