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

Molecular analyses allow one to determine genetic lesions occurring early in the development of tumors. With positional cloning approaches we are searching for a gene involved in the development of early onset familial breast and ovarian cancer that maps to human chromosome 17q21 and is termed BRCA1. This involves localizing the region genetically within families with multiply affected members, capturing the region identified by genetic analyses in YACs (yeast artificial chromosomes), converting those YACs to smaller manipulable pieces (such as cosmids), and searching for genes via a variety of approaches such as direct screening of cDNA libraries with genomic clones, direct selection by hybridization, "exon trapping", and CpG island rescue. Once identified, candidate genes will be screened for mutations in affected family members in whom breast cancer segregates with the locus on 17q21. The frequency of this gene has been calculated to be 0.0033; from this the incidence of carriers, i.e. those carrying such a predisposition, is one in 150 women. The isolation of BRCA1 and the elucidation of the mutations resulting in breast and ovarian cancer predisposition will allow identification of women who have inherited germ-line mutations in BRCA1. In families known to harbor a germ-line BRCA1 mutation, diagnosis of affected members will be rapid. It is possible that one will also be able to detect alterations of the second copy of this gene early in tumor development in individuals carrying a germ-line mutation. It is not yet known how frequently somatic BRCA1 mutations predispose to breast and ovarian carcinoma in the general female population. If, as in other genetic diseases, new germ-line mutations occur in some women and thus contribute to the development of breast cancer, it may be feasible to screen women in the general population for predisposing mutations. In addition, if acquired genetic mutations of the BRCA1 gene are involved as early events in the development of non-familial forms of the disease, early detection of possible breast carcinoma may become feasible in biopsy of breast tissue.
Breast Cancer Res Treat 1993 Nov
PMID:Molecular cloning of BRCA1: a gene for early onset familial breast and ovarian cancer. 817 65

Hereditary breast cancer (HBC) shows extant clinical and genetic heterogeneity. Clinically one finds the onset of breast cancer at an early age, an excess of bilaterality, and patterns of multiple primary cancer such as combinations of breast and ovarian carcinoma in the hereditary breast-ovarian cancer (HBOC) syndrome. In addition to HBOC, one sees a variety of putative breast cancer-prone genotypes inclusive of hereditary site-specific breast cancer, and the Li-Fraumeni (SBLA) syndrome that is characterized by cancers involving all three germinal layers including sarcomas, brain tumors, leukemia, lymphoma, and adrenal cortical carcinoma in addition to often markedly early-onset breast cancer. Breast cancer is also associated with autosomal dominantly inherited Cowden's disease and autosomal recessively inherited ataxia-telangiectasia. Examples of pedigrees depicting clinical examples of these several HBC syndromes are presented in order to describe HBC's heterogeneity. The recent identification of the BRCA1 gene in early-onset hereditary site-specific breast cancer and the HBOC syndrome has led to new challenges for the genetic counselor. We review genetic counseling, which embraces surveillance and management recommendations that are responsive to the natural history of HBC and address the concept for future development of centers of expertise for HBC in the interest of improving cancer control.
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PMID:Hereditary breast cancer and family cancer syndromes. 819 73

Recent reports suggest that subjects who are heterozygous for the ataxia-telangiectasia gene are at increased risk of breast cancer. We conducted linkage analyses of 64 families with premenopausal bilateral breast cancer using DRD2, a marker linked to the ataxia-telangiectasia locus at 11q22-23. We assumed a model with dominant transmission of breast cancer. Lod scores summed over all families provided strong evidence against tight linkage (e.g., a lod score of -6.08 at theta = 0.00001), although a single family provides suggestive evidence of tight linkage to DRD2. Evidence against linkage to 11q was strongest among families that may involve the BRCA1 breast cancer susceptibility gene on 17q21. However, we did not observe evidence of linkage to 11q among the remaining subgroup with neither a family history of ovarian cancer nor the appearance of linkage to 17q21.
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PMID:Linkage analysis of DRD2, a marker linked to the ataxia-telangiectasia gene, in 64 families with premenopausal bilateral breast cancer. 822 39

To facilitate the positional cloning of the breast-ovarian cancer gene BRCA1, we constructed a high-density genetic map of the 8.3-cM interval between D17S250 and GIP on chromosome 17q12-q21. Markers were mapped by linkage in the CEPH and in extended kindreds in our breast cancer series. The map comprises 33 ordered polymorphisms, including 12 genes and 21 anonymous markers, yielding an average of one polymorphism every 250 kb. Twenty-five of the markers are PCR-based systems. The order of polymorphic genes and markers is cen-D17S250-D17S518-HER2-THRA1-RARA-D17S80 -KRT10-[D17S800-D17S857]-GAS- D17S856-EDH17B-D17S855-D17S859-D17S858-[++ +PPY-D17S78]-D17S183-EPB3-D17S579- D17S509-[D17S508-D17S190 = D17S810]-D17S791-[D17S181 = D17S806]-D17S797- HOX2B-GP3A-[D17S507 = GIP]-qter. BRCA1 lies in the middle of the interval, between THRA1 and D17S183. Markers from this map can be used to determine whether cancer is linked to BRCA1 in families, to evaluate whether tumors have lost heterozygosity at loci in the region, and to identify probes for characterizing chromosomal rearrangements from patients and from tumors.
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PMID:High-density genetic map of the BRCA1 region of chromosome 17q12-q21. 824 78

A gene designated BRCA1, implicated in the susceptibility to early-onset familial breast cancer, has recently been localized to chromosome 17q12-q21. To date, the order of DNA markers mapped within this region has been based on genetic linkage analysis. We report the use of multicolor fluorescence in situ hybridization to establish a physically based map of five polymorphic DNA markers and 10 cloned genes spanning this region. Three cosmid clones and Alu-PCR-generated products derived from 12 yeast artificial chromosome clones representing each of these markers were used in two-color mapping experiments to determine an initial proximity of markers relative to each other on metaphase chromosomes. Interphase mapping was then employed to determine the order and orientation of closely spaced loci by direct visualization of fluorescent signals following hybridization of three probes, each detected in a different color. Statistical analysis of the combined data suggests that the order of markers in the BRCA1 region is cen-THRA1-TOP2-GAS-OF2-17HSD-248yg9-RNU 2-OF3-PPY/p131-EPB3-Mfd188- WNT3-HOX2-GP3A-tel. This map is consistent with that determined by radiation-reduced hybrid mapping and will facilitate positional cloning strategies in efforts to isolate and characterize the BRCA1 gene.
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PMID:Multicolor FISH mapping with Alu-PCR-amplified YAC clone DNA determines the order of markers in the BRCA1 region on chromosome 17q12-q21. 824 79

The chromosomal region 17q12-q21 contains a gene (BRCA1) conferring susceptibility to early-onset familial breast and ovarian cancer. An 8000-rad radiation-reduced hybrid (RH) panel was constructed to provide a resource for long-range mapping of this region. A large fraction of the hybrids (approximately 90%) retained detectable human chromosome 17 sequences. The complete panel of 76 hybrids was scored for the presence or absence of 22 markers from this chromosomal region, including 14 cloned genes, seven microsatellite repeats, and one anonymous DNA segment. Statistical analysis of the marker retention data employing multipoint methods provided both comprehensive and framework maps of this chromosomal region, including distance estimates between adjacent markers. The comprehensive RH map includes 17 loci and spans 179 cRays(8000). Likelihood ratios of at least 1000:1 support the 10-locus framework order: cen-D17S250-ERBB2-(THRA1, TOP2A)-D17S855-PPY-D17S190-MTBT1-GP3A++ +-BTR-D17S588-tel. The order obtained from RH mapping, when used in conjunction with other methods, will be useful in linkage analysis of breast cancer families and will facilitate the development of a physical map of this region.
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PMID:A radiation hybrid map of the BRCA1 region of chromosome 17q12-q21. 824 80

Up to 20 per cent of cases of breast cancer diagnosed in women under the age of 45 years may be caused by an autosomal dominant gene. A present difficulty is differentiation of mutation carriers from non-mutation carriers in high-risk families. Genetic linkage analysis has been used to localize a susceptibility gene (BRCA1) on chromosome 17q12-21 between markers 42D6 and MFD188, a region 5-10 million base pairs in length. Odds in favour of linkage to this region were greater than 100,000:1 in 15 families with breast cancer. In eight families in which the probability of linkage was above 75 (range 79.2-99.9) per cent, 19 women were identified who were at high lifetime risk of breast cancer (range 80.6-87.2 per cent) and 37 whose risk was similar to that for the general population (range 9.8-16.4 per cent). Genetic risk prediction of this kind may enable high-risk screening clinic resources to be concentrated on those most likely to benefit.
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PMID:Genetic linkage analysis applied to unaffected women from families with breast cancer can discriminate high- from low-risk individuals. 825 42

Efforts are under way to isolate a gene (BRCA1) on chromosome 17q12-21. Mutations in this gene predispose women to breast and ovarian cancer. Women with germline mutations in BRCA1 are estimated to have an 85% lifetime risk of developing breast cancer and an increased but as yet undetermined risk of ovarian cancer. It is estimated that one in 200 to 400 American women may be carriers of BRCA1 mutations. We have identified several families that show linkage between breast and/or ovarian cancer and genetic markers that flank BRCA1. It is now possible, within these linked families, to prospectively identify family members likely to be carrying BRCA1 mutations. Because of profound and immediate clinical ramifications, we offered to provide this information to one such extended family. To provide information to this family, we developed a protocol to address the many issues that arise in the delivery of these services. Although testing for BRCA1 mutation carriers is currently limited to very rare families being analyzed for research purposes, this experience presages the complexities of the much larger scale availability of population screening for BRCA1 mutations, which is likely to become a reality in the next few years.
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PMID:Genetic counseling for families with inherited susceptibility to breast and ovarian cancer. 835 30

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

A susceptibility gene for hereditary breast-ovarian cancer, BRCA1, has been assigned by linkage analysis to chromosome 17q21. Candidate genes in this region include EDH17B2, which encodes estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II), and RARA, the gene for retinoic acid receptor alpha. We have typed 22 breast and breast-ovarian cancer families with eight polymorphisms from the chromosome 17q12-21 region, including two in the EDH17B2 gene. Genetic recombination with the breast cancer trait excludes RARA from further consideration as a candidate gene for BRCA1. Both BRCA1 and EDH17B2 map to a 6 cM interval (between THRA1 and D17S579) and no recombination was observed between the two genes. However, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in four unrelated affected women did not uncover any sequence variation, other than previously described polymorphisms. Mutations in the EDH17B2 gene, therefore do not appear to be responsible for the hereditary breast-ovarian cancer syndrome. Single meiotic crossovers in affected women suggest that BRCA1 is flanked by the loci RARA and D17S78.
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PMID:Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA. 840 1


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