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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Breast cancer, one of the most common and deleterious of all diseases affecting women, occurs in hereditary and sporadic forms. Hereditary breast cancers are genetically heterogeneous; susceptibility is variously attributable to germline mutations in the BRCA1 (ref. 1), BRCA2 (ref. 2), TP53 (ref. 3) or ataxia telangiectasia (ATM) genes, each of which is considered to be a tumour suppressor. Recently a number of germline mutations in the BRCA2 gene have been identified in families prone to breast cancer. We screened 100 primary breast cancers from Japanese patients for BRCA2 mutations, using PCR-SSCP. We found two germline mutations and one somatic mutation in our patient group. One of the germline mutations was an insertion of an Alu element into exon 22, which resulted in alternative splicing that skipped exon 22. The presence of a 64-bp polyadenylate tract and evidence for an 8-bp target-site duplication of the inserted DNA implied that the retrotransposal insertion of a transcriptionally active Alu element caused this event. Our results indicate that somatic BRCA2 mutations, like somatic mutations in the BRCA1 gene, are very rare in primary breast cancers.
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PMID:Mutation analysis in the BRCA2 gene in primary breast cancers. 864 Feb 37

Approximately 20% of breast cancer patients have a family history of the disease, and in one-fourth of these cases breast cancer appears to be inherited as an autosomally dominant trait. Five genes and gene regions involved in breast cancer susceptibility have been uncovered. Germ-line mutations in the recently cloned BRCA1 gene at 17q21 is considered to be responsible for the disease in a majority of the breast-ovarian cancer families and in 40-45% of the site-specific breast cancer families, but appears not to be involved in families with both male and female breast cancer cases. The BRCA2 locus at 13q12-q13 appears to be involved in 40-45% of the site-specific breast cancer families, and in most of the families with affected males. The gene located in this region, however, does not seem to confer susceptibility to ovarian cancer. The TP53 gene is involved in breast cancer development in the Li-Fraumeni syndrome and Li-Fraumeni syndrom-like families, whereas germ-line mutations in the androgen receptor (AR) gene is present in a subset of male breast cancers. Furthermore, females who are obligate carriers of ataxia telangiectasia (AT) have a 4-12 times relative risk of developing breast cancer as compared with the general female population, indicating that germ-line mutations in AT also confer susceptibility to breast cancer.
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PMID:Genetic heterogeneity in breast cancer susceptibility. 869 52

Breast cancer is the most common form of cancer in women in the U.S. The risk factors for developing breast cancer include increasing age, a family history of breast cancer, and the lack of a child by age 30. A substantial fraction of breast cancer, however, occurs in women who have no identifiable risk factors. The diagnosis, pathology, treatment, and presymptomatic testing of cancer susceptibility genes are reviewed. Syndromes with an associated risk of breast cancer are described, such as hereditary breast-ovarian cancer syndrome, Li-Fraumeni syndrome, ataxia telangiectasia, and Cowden's disease. With the localization of the BRCA1 gene to chromosome 17q21 and the BRCA2 gene to chromosome 13q12, issues surrounding breast cancer susceptibility genetic testing are assuming an ever greater measure of importance. The sensitivity and specificity for molecular testing of cancer susceptibility genes, however, have not been well defined. The progress in presymptomatic genetic testing is further hampered by various factors such as the technical difficulty in distinguishing mutations from polymorphisms, the number of different mutations identified thus far and the possibility of false positive and false negative results. Laboratory quality assurance/quality control issues are of paramount importance to avoid misleading interpretations. Many issues surrounding genetic screening and testing, such as insurance and employment discrimination, privacy, and informed consent, are under active debate, and guidelines and standards are under active development. It is therefore important to proceed with caution, so that irreversible harm resulting from data misinterpretation can be avoided.
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PMID:Clinical and research issues in breast cancer genetics. 887 57

Two genes associated with a high breast cancer risk (BRCA1 and BRCA2) have been discovered recently from study of large breast-cancer-dense kindreds. It is problematic to make inferences from these atypical families to the general population. Nevertheless, it appears that about 1 to 2 per cent of all breast cancer may be due to rare deleterious mutations in BRCA1 or BRCA2. The majority of breast cancer families with fewer than four cases are likely to have cancers not attributable to these genes. There may be more common mutations in other genes (such as ATM, HRAS1) that confer a moderate risk of breast cancer, and may account for 5 to 15 per cent of cases. At this early stage of cancer genetics, the risks associated with particular mutations are not known, there are no proven and acceptable strategies for women with an inherited susceptibility to ameliorate risk or improve prognosis, and risk estimates appropriate for Australian women with a family history of breast cancer are not established, although data from the United States may overestimate risk. Information is needed from population-based studies, such as the Australian Breast Cancer Family Study (Hopper et al. Breast 1994; 3: 79-86), but 100 per cent mutation detection in large cancer genes is difficult and expensive. Development of a systematic, research-oriented, evidence-based approach to genetic testing in Australia is recommended. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database.
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PMID:Some public health issues in the current state of genetic testing for breast cancer in Australia. 898 9

Familial breast cancer is characterized by young age at diagnosis, an increased risk of bilateral breast cancer, an increasing risk in conjunction with increasing numbers of affected family members, and a strong association with ovarian cancer. At least eight candidate breast cancer susceptibility genes have been identified. Mutations in BRCA1, BRCA2, p53, and the Cowden disease gene are relatively uncommon, are highly penetrant, and produce striking familial clusters of breast cancer. BRCA1 and BRCA2 are the most important of these, accounting for an estimated 80% of hereditary breast cancer and 5 to 6% of all breast cancers. Specific BRCA1 and BRCA2 mutations are of particular importance in population subgroups, such as those identified among Jewish women of central European (Ashkenazi) origin. Mutations in the ataxia-telangiectasia gene and the rare HRAS1 variable number of tandem repeats polymorphisms are much more common but also much less penetrant. They do not produce dramatic familial aggregations of breast cancer but may prove to be responsible for a substantial proportion of all breast cancers if their epidemiologic association with breast cancer is confirmed. Predictive genetic testing for breast cancer risk is under way. Oncologists and primary-care physicians must become familiar with these genetic disorders and the issues surrounding predictive testing in order to make appropriate management decisions about women thought to have a high genetic risk of breast cancer.
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PMID:Genetics of breast cancer. 900 88

To appreciate the involvement of known or potential susceptibility genes in sporadic breast tumors, we have searched for chromosomal deletions by studying loss of heterozygosity (LOH) at 43 microsatellite (CA)n markers from human chromosomes 10, 11 and 17, in 115 unselected consecutive samples of breast carcinoma with particular emphasis on specific regions. No site of consistent LOH was identified on chromosome 10. Five regions of LOH were contained within bands q22-24 of chromosome 11 for which nearly 50% of the tumors had LOH at at least one marker. This region is thus a major site of deletion in breast cancer and several tumor suppressor genes seem to be involved. One of them may be the ataxia telangiectasia (ATM) gene which is located in one of the affected regions. Five regions of LOH, one of which is within the BRCA1 gene area, were recognized along chromosome 17. LOH at three of these regions were found in highly proliferative tumors. When combined with a previous study of chromosome 13 with emphasis on BRCA2 and Rb1 genes, this work allowed to distinguish a total of 12 regions of LOH, variably affected in breast tumors and correlated with prognostic parameters.
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PMID:Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions. 901 20

Breast cancer is the most common malignancy among women. Genetic predisposition is considered to account for 5-10% of all cases while the majority of these cancers are sporadic and caused by complex interactions of exogenous and endogenous factors. The inherited predisposition can be due to germline mutations in one of several cancer susceptibility genes. For high risk families the two most important genes are BRCA1 on chromosome 17q, which confers a high risk of both, breast and ovarian cancer and BRCA2 on chromosome 13 associated with high penetrance of breast cancer but lower risk of ovarian cancer. A high risk of breast cancer is conferred by mutations in the p53 tumor suppressor gene as part of the rare Li-Fraumeni-syndrome, and possibly also by the estrogen receptor gene. Other cancer genes associated with a less increased risk of breast cancer are the autosomal recessive ataxia telangiectasia (AT) gene and the HRAS1 gene. Germline mutations in BRCA1 and BRCA2 account for the majority of families with multiple cases of breast and/or ovarian cancer and also at least 10% of cases below the age of 40 years. Genetic testing for BRCA1 mutations is not generally recommended except for women with a strong family history. The aim for the management of familial breast cancer should be the establishment of interdisciplinary teams to cover genetic counseling, molecular analysis, onco-surgical therapy, psychosocial support and clinical follow-up.
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PMID:[Molecular genetics of hereditary breast carcinoma]. 917 60

Sporadic breast carcinoma is associated with multiple genetic alterations. The clinical relevance of these alterations, however, needs further clarification. In the present study we analyzed 266 spontaneously arising breast carcinomas for allelic losses in the BRCA1 and TP53 regions on chromosome 17, the BRCA2 region on chromosome 13, the ATM (mutated in ataxia-telangiectasia) region on chromosome 11 and on the chromosomal arms 7q and 16q. In addition the following clinical and pathological parameters were evaluated: age at diagnosis, tumor size, presence or absence of regional and distant metastases, hormone-receptor status, histopathological classification and tumor grading. The analysis of genetic and clinical observations revealed significant associations: absence of expression of the estrogen receptor was linked to a high rate of allelic losses of markers in the BRCA1, TP53 and BRCA2 regions. Expression of the progesterone receptor coincided with allelic loss on the long arm of chromosome 16. High-grade malignant lesions and ductal differentiation were frequently associated with allelic losses in the proximal portion of chromosome 17q. The accumulation of multiple allelic deletions was linked to high-grade malignant tumors, to tumor size, and to loss of expression of the estrogen receptor. Our data point to a relationship between clinically relevant prognostic factors and specific genomic deletions in the BRCA1, BRCA2 and TP53 region.
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PMID:Genomic deletions in the BRCA1, BRCA2 and TP53 regions associate with low expression of the estrogen receptor in sporadic breast carcinoma. 922 12


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