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

Recent advances in our understanding of the genetic characteristics of cancer will change approaches to genetic screening and counselling. Cancer results from multiple, cumulative mutations in genes that regulate cell replication and differentiation. In familial cancer a germ-line mutation is passed on in an autosomal dominant pattern, but cancer will develop in people who inherit the defect only if other mutations also occur in susceptible somatic cells. The tumour-suppressor gene known as BRCA1 is thought to affect half of those families who have an inherited breast cancer syndrome and most families with a breast and ovarian cancer syndrome. Another gene, BRCA2, is thought to affect most of the remaining families with a breast-cancer-only syndrome. Hereditary nonpolyposis colon cancer (HNPCC) is caused by mutations in surveillance genes that protect DNA from the spontaneous errors that occur during cell division. Because there are no outcome data on which to base practice guidelines for genetic screening or management of asymptomatic carriers in families at risk, testing should be restricted to research settings.
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PMID:Genetic counselling and testing for susceptibility to breast, ovarian and colon cancer: where are we today? 854 3

Interest in the genetics of breast cancer has intensified with the discovery of a breast cancer susceptibility locus, BRCA1, on chromosome 17q. In this paper, we describe updated information on a large breast cancer kindred (K107) that has been extensively studied since 1948. Specifically, we have identified many new cases of cancer in the family and have shown that this family is unlinked to BRCA1 as well as a number of other genes considered as candidates for breast cancer. In a collaborative study between the University of Utah and the Institute of Cancer Research in the United Kingdom, we have collected a set of families with a predisposition to breast and ovarian cancers that have been reliably excluded from linkage to BRCA1 and evaluated their usage in a genomic search for other breast cancer loci. This effort led to the discovery of a second breast cancer locus located on chromosome 13q, BRCA2, which is responsible for the increased incidence of breast cancer in Kindred 107.
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PMID:A 45-year follow-up of kindred 107 and the search for BRCA2. 857 46

Prophylactic mastectomy, intensified breast cancer screening, and the use of chemopreventive agents have all been recommended to reduce breast cancer risk in women with a family history of breast cancer. Yet, little is currently known about the efficacy of these approaches in reducing breast cancer mortality. The recent identification of BRCA1 and the localization of BRCA2 lend urgency to the need to assess breast cancer intervention and prevention strategies for women likely to carry germline mutations at these loci. At present, families with a history consistent with a BRCA1 or BRCA2 mutation should be tested within the confines of a research protocol and encouraged to participate in intervention and prevention trials. Both retrospective studies and prospective clinical trials are critically needed. While randomized clinical trials would be the optimal mechanism to assess the relative efficacy of these potential interventions, no consensus was obtained as to whether such a trial would be feasible because of strong patient preference for intervention type. It is likely that optimal intervention and prevention strategies will consist of a combined approach to risk reduction. Participants must be appropriately informed of the potential risks as well as the potential benefits of such testing. The potential risks of testing for genetic susceptibility include not only potential psychosocial harm that may result from learning one's carrier status, but also the potential for altered family relationships and insurance and job discrimination. Participants and their family members must be counseled concerning the implication of their test results.
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PMID:Developing strategies for intervention and prevention in hereditary breast cancer. 857 65

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.
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PMID:The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. 858 4

The etiology of breast cancer involves a complex interplay of various factors, including genetic alterations. Many studies have been devoted to the identification and characterization of mutations that occur frequently during breast tumorigenesis. The major types of genetic abnormalities that are frequently observed in breast tumors are amplification of protooncogenes (MYC, ERBB2) and DNA from chromosome band 11q13; mutation of TP53; and loss of heterozygosity from chromosomes and chromosome arms 1, 3p, 6q, 7q, 8p, 11, 13q, 16q, 17, 18q, and 22q. The latter may correspond to losses or inactivations of tumor suppressor genes. Recently, linkage analyses of large families with a predisposition to breast cancer have been performed in order to map breast cancer susceptibility genes (TP53, BRCA1, BRCA2). The findings have thrown light on the molecular mechanisms of breast cancer and have enabled various genetic markers to be used in clinical oncology.
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PMID:Genetic alterations in breast cancer. 860 12

Five to ten percent of breast cancer is attributable to the autosomal dominant inheritance of a high-risk susceptibility gene. There are a number of known inherited cancer syndromes that confer a higher risk of breast cancer. Recently, the BRCA1 gene, which is responsible for 45% of hereditary early-onset breast cancer and for the majority of co-inheritance of breast and ovarian cancer, has been cloned. Another gene that confers an increased risk of breast cancer is the BRCA2 gene, which maps to the long arm of chromosome 13 by linkage analysis. Mutations in BRCA2 account for approximately 40% of hereditary early-onset breast cancer. In addition, at least 7% of breast cancer may occur in women who are heterozygous for mutations in a gene for ataxia-telangiectasia, an autosomal recessive chromosome instability syndrome. Predictive testing for some predisposing conditions is possible through indirect or direct mutation testing. In this article, the genetics of breast cancer are reviewed, and practical concerns for the surgeon in counseling high-risk patients are addressed.
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PMID:Inherited breast cancer. 861 Feb 59

Because studies of breast cancer patients and their relatives provide statistical evidence for involvement of autosomal dominant genes, the identification of specific genetic effects has long been the focus of efforts to identify women at exceedingly high risk. BRCA1, a gene that confers greatly increased susceptibility to breast and ovarian cancer, was isolated in 1994, capping an intense analysis by a large number of groups of a complex phenotype. BRCA1 is a large gene and shows only limited homology to other known genes. Near the amino terminus of the predicted protein is a RING finger motif. In addition, a leucine heptad repeat appears in the interior of the sequence. Several groups have looked extensively for somatic BRCAI mutations in breast and ovarian tumors. The frequency of somatic mutations in ovarian tumors is low, and to date no somatic mutations have been found in breast tumors. More research is needed to define the role of BRCA1 in sporadic tumors. A second locus associated with predisposition to early onset breast cancer, BRCA2, has been localized to chromosome 13q. Positional cloning of this gene is well advanced and analysis of its biology and mutation spectrum is eagerly awaited. As the BRCA1 and BRCA2 genes are characterized further, a diagnostic test for breast cancer susceptibility becomes feasible.
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PMID:THe genetics of familial breast cancer. 861 40

Recently, the breast cancer susceptibility gene BRCA2 has been identified in chromosome 13q, a region that also contains the retinoblastoma gene RB1. To elucidate a possible role of BRCA2 and RB1 in sporadic breast tumorigenesis, allelic imbalance (AI) at 13q loci was examined in 78 primary sporadic breast tumors. AI was found in 52-63% of tumors. Nine tumors showed AI only in the BRCA2 region but not at RB1. Six tumors showed AI at RB1 but not in the BRCA2 region. AI in the BRCA2 region correlated significantly with aneuploidy (P = 0.032) and AI at RB1 with small tumor size (P = 0.025). Our data suggest that BRCA2 and RB1 may be both distinct target loci for AI on chromosome 13 in sporadic breast cancer.
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PMID:Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer. 861 37

The development of familial and sporadic breast cancer is based on genetic alterations of tumour-suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation. To investigate LOH of BRCA1 (17q21) and BRCA2 (13-q12-13) in sporadic breast cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for detection of microsatellite polymorphisms was applied. A total of 137 breast cancer and 15 benign breast specimens with matched normal tissue were examined. Fluorescent-labelled PCR products were analysed in an automated DNA sequencer (ALFTM Pharmacia). Losses at both loci were correlated with different histological types, age, tumour size, lymph node status, grading and steroid hormone receptor expression, [SHR: oestrogen receptor (ER), progesterone receptor (PgR)]. For BRCA1 (D17S855, THRA1, D17S579) losses could be detected in invasive ductal carcinoma (IDC; n = 108) in 32-38%, invasive lobular carcinoma (ILC; n = 19) in 21-42% depending on the marker applied, but not in benign breast tumours (n = 15). Losses of BRCA1 markers correlated with larger tumour size, higher grade, and PgR expression. For BRCA2 (D13S260, D13S267, D13S171) losses could be detected in 108 IDCs in 30-38%, in 19 ILCs in 17-39% depending on the marker applied, but not in benign breast tumours. Losses of BRCA2 markers correlated only with higher grade. Microsatellite analyses combined with detection of fluorescent-labelled PCR products by an automated laser DNA sequencer can be used for routine determination of LOH. In sporadic breast cancer, LOH of BRCA1 of BRCA2 does not add decisive prognostic value as stated for familial breast cancer.
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PMID:Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. 863 Feb 82

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.
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PMID:BRCA2 mutations in primary breast and ovarian cancers. 864 Feb 35


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