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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The breast cancer susceptibility gene, BRCA1, was isolated in 1994. Recent investigations into the genetic epidemiology of BRCA1 have revealed an unexpectedly high prevalence of mutations amongst Ashkenazi Jews. Analyses of BRCA1 function have indicated that it may act as an inhibitor of cell proliferation and is necessary for normal development in the mouse. The presence of a motif in BRCA1 characteristic of a family of proteins known as granins, has led to the suggestion that the protein is secreted into the extracellular space. The BRCA2 gene has recently been identified. BRCA2 encodes a large protein of 3418 amino acids without strong homology to any other protein in the database. However, BRCA2 also contains a putative granin motif and a different eight times repeated motif of unknown function. In addition to breast and ovarian cancer, germline BRCA2 mutations probably confer a small risk of a wide range of cancers. Somatic mutations of BRCA2 in sporadic breast and ovarian cancer are very rare. The gene for Cowden syndrome has recently been located and it will now be possible to assess whether it is responsible for the set of families not accounted for by BRCA1 and BRCA2.
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PMID:Recent advances in understanding of genetic susceptibility to breast cancer. 887 58

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

Germline mutations in BRCA2 predispose carriers to the development of breast, ovarian, and a variety of other cancers. The original localization of the BRCA2 gene was aided by its homozygous deletion in a pancreatic carcinoma; indeed, an excess of pancreatic carcinoma has been seen in some BRCA2 cancer families. To determine the involvement of BRCA2 in pancreatic carcinomas, we screened for BRCA2 alterations in an unselected panel of 41 adenocarcinomas of the pancreas (30 pancreatic adenocarcinoma xenografts and 11 pancreatic cancer cell lines). Of the 15 (27%) that had allelic loss at the BRCA2 locus, 4 (9.8%) had abnormalities in the second allele upon screening of the entire BRCA2 gene by in vitro synthesized protein assay. Three of the four mutations were considered germline in origin (7.3% overall; two were confirmed in normal tissue, and one was the 6174delT mutation from the pancreatic cancer cell line CAPAN-1, for which normal tissue was unavailable). The identification of two 6174delT mutations in this series prompted us to evaluate the prevalence of this mutation in an overlapping consecutive series of 245 patients who underwent pancreatoduodenectomy for adenocarcinoma of the pancreas. Sequence analysis of this limited region of the gene identified two additional mutations: (a) one additional germline 6174delT mutation (2 of 245, 0.8% overall); and (b) a second nearby germline 6158insT mutation. One of the patients with a germline mutation had a single relative with breast cancer, and another had a single relative with prostate cancer. None had a family history of pancreatic cancer. The incidence of germline BRCA2 mutations in apparently sporadic pancreatic cancer may be at least as high as in breast or ovarian cancer. Our results suggest that some familial risks for carcinoma will be evident only through a population-based application of gene screening techniques because a low disease penetrance of the germline mutations in some families often evades clinical suspicion.
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PMID:Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. 896 85

Between 5% and 10% of breast cancer cases can be traced to primary genetic factors. Before the discovery of the BRCA1 and BRCA2 genes, if a first-degree relative in direct genetic lineage had hereditary breast cancer or hereditary breast-ovarian cancer syndrome, the best estimate of family members' genetic risk for breast cancer was 50%. Now the lifetime cancer destiny of a patient who carries a BRCA1 or BRCA2 germ line mutation can be determined with an extraordinary degree of precision. However, a major concern facing clinicians is how to use this powerful genetic knowledge without harming the patient. This presentation focuses on the need for (a) compilation of a detailed family history of cancer of all anatomic sites; (b) understanding of the natural history of hereditary breast cancer and its heterogeneous forms and the pathobiology of hereditary breast cancer; and (c) preparation for performance of genetic counseling that is based on the results of DNA sequencing to detect genes related to cancer susceptibility. The discussion addresses the advantages of this molecular genetic movement, which include the abilities (a) to predict who is and who is not at inordinately high risk for cancer; (b) to provide opportunities for highly targeted disease surveillance and management; (c) to give patients the information they need to make appropriate long-term decisions about matters such as procreation; and (d) to give genetic counselors the information they need to appreciate the emotions patients may encounter, such as fear, anxiety, and apprehension, and the ordeal of being subjected to discrimination by insurance companies and employers.
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PMID:Breast cancer genetics: family history, heterogeneity, molecular genetic diagnosis, and genetic counselling. 897 6

The breast cancer susceptibility gene BRCA2 on chromosome 13q12-13 has recently been identified. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. Germline mutations of a second cancer susceptibility gene BRCA1 (ref. 5), are associated with a strong predisposition to ovarian cancer as well as female breast cancer. Recent studies have suggested that the phenotype in BRCA1 families with respect to the ratio of breast to ovarian cancer varies with the location of the BRCA1 mutation. To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have analysed the distribution of mutations in 25 families with multiple cases of breast and/or ovarian cancer ascertained in the United Kingdom and Eire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Analysis of the mutation distribution along the length of the gene indicates a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a region of approximately 3.3 kb in exon 11 (P = 0.0004). Published data on mutations in 45 other BRCA2-linked families provide support for this correlation.
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PMID:Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. 898 79

The tumor suppressor genes BRCA1 and BRCA2, which confer increased susceptibility to breast and (or) ovarian cancer, were recently identified. Mutation analysis of BRCA1 has demonstrated significant allelic heterogeneity; however, some distinct mutations have been detected in unrelated individuals. The most notable is the 185delAG mutation, which occurs at an estimated frequency of approximately 1% in individuals of Ashkenazi Jewish descent [1]. Although consensus has not been reached regarding clinical testing for mutations in BRCA1, a tiered strategy may be appropriate, in which direct testing for the more common mutations is one component. Specific alleles can be detected by using PCR-mediated site-directed mutagenesis (PSM), which alters the PCR products derived from either the wild-type or mutant allele to create or destroy a restriction endonuclease recognition site. Recognition sites are introduced by a base substitution in one of the primers. The alleles are then resolved by electrophoresis of the digested PCR products. We have applied this technique to the detection of four BRCA1 mutations: 185delAG, 5382insC, E1250X, and R1443X. Another mutation, 1294de140, can be resolved from the wild-type allele by high-resolution gel electrophoresis alone. The PSM technique is sensitive, does not require radioactivity, and is specific for individual mutations.
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PMID:Direct detection of mutations in the breast and ovarian cancer susceptibility gene BRCA1 by PCR-mediated site-directed mutagenesis. 899 Feb 12

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

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.
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PMID:Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. 901 4

The recent identification of genes that predispose their carriers to breast and ovarian cancer promises to shed light on the biology of cancer susceptibility. Individuals with mutations in the BRCA1 gene on chromosome 17 and the BRCA2 gene on chromosome 13 have four to eight times the risk of developing breast cancer as women in the general population. The many mutations that have been identified in both genes are predicted to produce a truncated, presumably nonfunctional, protein. Individuals of Ashkenazi Jewish decent have been found to carry specific BRCA1 and BRCA2 mutations. The sequences of BRCA1 and BRCA2 are not similar to any other previously cloned genes. Investigations are underway to elucidate the biological function of these genes. In the meantime, these genes offer the opportunity for members of high incidence cancer families to decide whether to undergo predisposition testing. There is a paucity of data to guide physicians in making follow-up recommendations to those who are found to be carrying a mutation. Thus, decisions about testing are personal and demand pretest education and counseling about the risks, benefits, and limitations. Further research into testing decisions and their outcome is greatly needed.
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PMID:Genetic susceptibility testing for breast and ovarian cancer: a progress report. 903 68

Epidemiologic data support the existence of two discrete manifestations of hereditary ovarian carcinoma: the breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Genetic linkage analyses reveal that the majority of breast and ovarian cancer families are linked to the BRCA1 gene, while some cases of hereditary ovarian cancer are also apparent in breast cancer families linked to the BRCA2 gene. The majority of HNPCC families are linked to one of four genes encoding a family of DNA mismatch repair proteins. Molecular analyses demonstrate that genetic screening for germline transmission of a defective allele of one or another of these genes is now possible for high-risk individuals. The ethical, legal, and social implications of this type of analysis are multiple and complex, and genetic counseling requires a thorough understanding of these issues and a cautious approach to most effectively meet the special needs of this patient population. Increased medical surveillance and prophylactic oophorectomy are among the management options that may be appropriate for some genetically predisposed, asymptomatic women. Further research is needed regarding the most effective use of this genetic information in formulating counseling and clinical management strategies.
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PMID:Hereditary ovarian cancer: molecular genetics and clinical implications. 903 64


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