Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.
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PMID:Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. 1063 95

Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity.
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PMID:Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. 1070 25

The medical histories of breast cancer-prone families have been described for over a century. The pattern of breast cancer occurrences in these families is most consistent with an autosomal dominant mode of inheritance. The location of a gene that could explain the pattern of transmission of the breast cancer trait in families averaging early (pre-menopausal) onset of breast cancer was reported in 1990. Since then, two genes have been identified: BRCA1 and BRCA2. Germ-line mutations in these two genes confer susceptibility to breast (female and male) and ovarian cancer, and account for a significant proportion of hereditary breast cancer in two cancer syndromes: site-specific breast cancer and the breast-ovarian cancer syndrome. Other hereditary syndromes that feature breast cancer are Li-Fraumeni syndrome, Cowden disease, and ataxia telangiectasia, whose carriers have been shown to harbor germ-line mutations in TP53, PTEN, and ATM, respectively. There may be other genetic factors that contribute to hereditary breast cancer, since not all families with multiple cases of breast cancer harbor germ-line BRCA1 or BRCA2 mutations. Host factors (such as lifestyle choices) and other genes may modulate risk of breast cancer in mutation carriers.
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PMID:Genes implicated in hereditary breast cancer syndromes. 1080 49

Genetic testing has been widely available and useful in several kinds of familial cancer. Shinshu University Hospital established a division of clinical and molecular genetics as one of its central service departments. We have a staff meeting once a week to discuss each case to provide the suitable counseling and the ethical-legal and social issues. We performed genetic testing in 44 cases, including familial adenomatous polyposis, multiple endocrine neoplasia type 1 and 2, familial breast cancer, von Hippel-Lindau disease, and Li-Fraumeni syndrome. This is the first clinical genetics department in the National University Hospitals in Japan and this system increases the utility of genetic testing.
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PMID:[Hereditary cancer and genetic testing: the role of division of clinical and molecular genetics]. 1087 51

Germ-line mutations in BRCA1 and BRCA2 genes result in a significantly increased risk of breast and ovarian cancer. Other genes involved in an increased predisposition to breast cancer include the TP53 gene, mutated in Li-Fraumeni syndrome. To estimate the frequency of germ-line mutations in these three genes in Upper Silesia, we have analyzed 47 breast/ovarian cancer families from that region. We found five different disease predisposing mutations in 17 (36%) families. Twelve families (25.5%) carried known BRCA1 mutations (5382insC and C61G), four families (8.5%) carried novel BRCA2 mutations (9631delC and 6886delGAAAA), and one family (2%) harbored novel mutation 1095del8 in the TP53 gene, which is the largest germline deletion in coding sequence of this gene identified thus far. The 5382insC mutation in BRCA1 was found in 11 families and the 9631delC mutation in BRCA2 occurred in three families. These two mutations taken together contribute to 82% of all mutations found in this study, and 30% of the families investigated harbor one of these mutations. The very high frequency of common mutations observed in these families can only be compared to that reported for Ashkenazi Jewish, Icelandic, and Russian high-risk families. This frequency, however, may not be representative for the entire Polish population. The observed distribution of mutations will favor routine pre-screening of predisposed families using a simple and cost-effective test.
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PMID:High frequency of recurrent mutations in BRCA1 and BRCA2 genes in Polish families with breast and ovarian cancer. 1110 77

Breast cancer is the most frequent tumor type among women in the United States and in individuals with Li-Fraumeni syndrome. The p53 tumor suppressor gene is altered in a large proportion of both spontaneous breast malignancies and Li-Fraumeni breast cancers. This suggests that loss of p53 can accelerate breast tumorigenesis, yet p53-deficient mice rarely develop mammary tumors. To evaluate the effect of p53 loss on mammary tumor formation, the p53(null) allele was back-crossed onto the BALB/c genetic background. Median survival was 15.4 weeks for BALB/c-p53(-/-) mice compared to 54 weeks for BALB/c-p53(+/-) mice. Sarcomas and lymphomas were the most frequent tumor types in BALB/c-p53(-/-) mice, whereas 55% of the female BALB/c-p53(+/-) mice developed mammary carcinomas. The mammary tumors were highly aneuploid, frequently lost the remaining wild-type p53 allele, but rarely lost BRCA1. Although mammary tumors were rarely detected in BALB/c-p53(-/-) female mice, when glands from BALB/c-p53(-/-) mice were transplanted into wild-type BALB/c hosts, 75% developed mammary tumors. The high rate of mammary tumor development in the BALB/c background, but not C57Bl/6 or 129/Sv, suggests a genetic predisposition toward mammary tumorigenesis. Therefore, the BALB/c-p53(+/-) mice provide a unique model for the study of breast cancer in Li-Fraumeni syndrome. These results demonstrate the critical role that the p53 tumor suppressor gene plays in preventing tumorigenesis in the mammary gland.
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PMID:Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. 1110 87

Clinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.
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PMID:Genetic testing for cancer predisposition. 1116 Jul 85

Recently CHK2 was functionally linked to the p53 pathway, and mutations in these two genes seem to result in a similar Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFL) multi-cancer phenotype frequently including breast cancer. As CHK2 has been found to bind and regulate BRCA1, the product of one of the 2 known major susceptibility genes to hereditary breast cancer, it also more directly makes CHK2 a suitable candidate gene for hereditary predisposition to breast cancer. Here we have screened 79 Finnish hereditary breast cancer families for germline CHK2 alterations. Twenty-one of these families also fulfilled the criteria for LFL or LFS. All families had previously been found negative for germline BRCA1, BRCA2 and TP53 mutations, together explaining about 23% of hereditary predisposition to breast cancer in our country. Only one missense-type mutation, Ile(157)-->Thr(157), was detected. The high Ile(157)--> Thr(157)mutation frequency (6.5%) observed in healthy controls and the lack of other mutations suggest that CHK2 does not contribute significantly to the hereditary breast cancer or LFL-associated breast cancer risk, at least not in the Finnish population. For Ile(157)--> Thr(157)our result deviates from what has been reported previously.
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PMID:Mutation analysis of the CHK2 gene in families with hereditary breast cancer. 1146 Oct 78

A woman with a family history of brain tumors in her daughter and sister presented with a breast cancer. She subsequently developed two metachronous primary tumors: a small-cell lung cancer and a colon carcinoma. These tumors arose within the internal mammary radiotherapy field and within the field irradiated for ovariolysis. The p53 gene was analyzed in whole blood lymphocytes using a functional assay developed in yeast Saccharomyces cerevisiae, which tests the transcriptional competence of p53. DNA from the colon cancer cells was analyzed by polymerase chain reaction and sequencing. The patient had a germline-inactivating p53 mutation, confirming the diagnosis of Li-Fraumeni syndrome (LFS). The colon tumor and the lung tumor both conserved the mutant p53 allele but had lost the wild-type allele. This observation and the experimental data suggest an abnormal sensitivity of LFS patients to radiogenic carcinogenesis. The indications and extent of radiotherapy in patients with a clinical or molecular diagnosis of LFS should be discussed individually and should take into account the risk of secondary neoplasms arising in the radiation fields.
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PMID:Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. 1147 98

Many polymorphisms have been reported in the TP53 gene. Some of these are within the coding region, and may affect the function of the p53 protein, others are within introns or non-coding regions, and their significance is unclear. Recently, a number of publications have claimed that polymorphisms within intron 6 are responsible for inherited predisposition to childhood malignancies, familial breast cancer, and Li-Fraumeni syndrome (LFS). We find no evidence for intron 6 sequence variants predisposing to LFS in our cohort of families and, furthermore, we show that some of the conclusions of other groups cannot be supported by data from our analysis.
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PMID:Significance of intron 6 sequence variations in the TP53 gene in Li-Fraumeni syndrome. 1152 May 73


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