Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analysed 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene, using single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. A total of eight putative disease-causing alterations were identified: four of these are frameshifts and two are nonsense mutations. In addition, we found two missense mutations, one of which changes the final cysteine of the BRCA1 zinc finger motif to glycine. These data are consistent with a tumour suppressor model, and support the notion that this candidate gene is in fact BRCA1. The heterogeneity of mutations, coupled with the large size of the gene, indicates that clinical application of BRCA1 mutation testing will be technically challenging.
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PMID:Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. 789 91

Women who carry mutations in the BRCA1 gene on chromosome 17q have an 85% lifetime risk of breast cancer, and a 60% risk of ovarian cancer. We have identified BRCA1 mutations in 12 of 30 (40%) Canadian families with breast and/or ovarian cancer, including six of the eight families (75%) that contained two cases of early-onset breast cancer and two cases of ovarian cancer. Six frameshift mutations account for all 12 mutant alleles, including nucleotide insertions (two mutations) and deletions (four mutations). Four independent families carried the same 1 basepair (bp) insertion mutation in codon 1755 and four other families shared a 2 bp deletion mutation in codons 22-23. These families were not known to be related, but haplotype analysis suggests that the carriers of each of these mutations have common ancestors.
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PMID:Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. 789 92

We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.
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PMID:Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. 789 93

Germline mutations in a gene on chromosome 17q known as BRCA1 are responsible for a large proportion of inherited predispositions to breast and ovarian cancer. In 33 families with evidence of linkage to BRCA1, we estimated the risks of breast and ovarian cancer from the occurrence of second cancers in individuals with breast cancer, and examined the risks of other cancers in BRCA1 carriers. 26 contralateral primary breast cancers occurring more than 3 years after a first breast cancer were observed before age 70, giving an estimated cumulative risk of breast cancer in gene carriers of 87% by age 70.23 primary ovarian cancers occurred in women with a previous breast cancer, resulting in an estimated cumulative risk of ovarian cancer of 44% by age 70.87 cancers other than breast or ovarian cancer were observed in individuals with breast or ovarian cancer and their first-degree relatives compared with 69.3 expected, based on national incidence rates. Significant excesses were observed for colon cancer (estimated relative risk [RR] to gene carriers 4.11 [95% CI 2.36-7.15]) and prostate cancer (3.33 [1.78-6.20]). No significant excesses (or deficits) were noted for cancers of other sites. Our study provides estimates of breast and ovarian cancer risks which are useful for counselling BRCA1-mutation carriers. It also shows that carriers are at increased risk of colon and prostate cancer, which may be of clinical significance in certain families if the risks are associated with specific mutations.
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PMID:Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. 790 78

The past year has seen a great deal of excitement in the field of breast cancer genetics. Since linkage of the familial breast-ovarian cancer gene (BRCA1) to chromosome 17, the critical region has been narrowed to 1.0-1.5 Mb by recombination studies, a detailed physical map has been constructed and much of the region has been cloned in yeast artificial chromosome, bacteriophage P1 and cosmid vectors. The focus now lies on identifying the genes housed within the BRCA1 region and scanning them for oncogenic mutations.
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PMID:Towards cloning the familial breast-ovarian cancer gene on chromosome 17. 791 22

Linkage analysis in familial breast and ovarian cancer and studies of allelic deletion in sporadic ovarian tumors have identified a region on chromosome 17q containing a candidate tumor-suppressor gene (referred to as BRCA1) of likely importance in ovarian carcinogenesis. We have examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of the disease, for loss of heterozygosity (LOH) at 21 loci on chromosome 17 (7 on 17p and 14 on 17q). LOH on 17p was 55% (22/40) for informative 17p13.1 and 17p13.3 markers. When six polymorphic markers flanking the familial breast/ovarian cancer susceptibility locus on 17q12-q21 were used, LOH was 58% (23/40), with one tumor showing telomeric retention. Evaluation of a set of markers positioned telomeric to BRCA1 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to BRCA1. Five of the tumors demonstrating allelic loss for 17q markers were from individuals with a strong family history of breast and ovarian cancer. More important, two of these tumors (unique patient number [UPN] 57 and UPN 79) retained heterozygosity for all informative markers spanning the BRCA1 locus but showed LOH at loci distal to but not including the anonymous markers CMM86 (D17S74) and 42D6 (D17S588), respectively. Deletion mapping of seven cases (two familial and five sporadic) showing limited LOH on 17q revealed a common region of deletion, distal to GH and proximal to D17S4, that spans approximately 25 cM. These results suggest that a potential tumor-suppressor gene involved in both sporadic and familial ovarian cancer may reside on the distal portion of chromosome 17q and is distinct from the BRCA1 gene.
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PMID:A common region of deletion on chromosome 17q in both sporadic and familial epithelial ovarian tumors distal to BRCA1. 794 44

We have constructed a physical map of a 4 cM region on chromosome 17q12-21 that contains the hereditary breast and ovarian cancer gene BRCA1. The map comprises a contig of 137 overlapping yeast artificial chromosomes and P1 clones, onto which we have placed 112 PCR markers. We have localized more than 20 genes on this map, ten of which had not been mapped to the region previously, and have isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. Two genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients have been sequenced in breast cancer patients without revealing any deleterious mutations. These new reagents should facilitate the identification of BRCA1.
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PMID:A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21. 795 16

BRCA1, a breast-ovarian cancer susceptibility gene which has been localized to 17q21, appears to be a tumor suppressor gene based on evidence from loss of heterozygosity (LOH) studies. We analyzed 14 ovarian and breast tumors from BRCA1 carriers and 1 sporadic breast tumor from 3 kindreds for 17q21 LOH. Thirteen of the 14 tumors from gene carriers exhibited LOH of the wild-type allele. Tumors from one gene carrier and the sporadic breast case did not exhibit any LOH in the region. There was loss of the wild-type allele from both maternally and paternally derived chromosomes, therefore excluding the possibility of genomic imprinting and providing further evidence that BRCA1 is a tumor suppressor. Three tumors showed interstitial LOH in the region, and thus established the utility of familial tumors in refining a region surrounding a tumor suppressor gene in a manner analogous to using genetic recombinants.
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PMID:Loss of heterozygosity in familial tumors from three BRCA1-linked kindreds. 795 48

Multiple specific chromosomal deletions can be found in human epithelial ovarian cancer by cytogenetic analysis or molecular techniques. Somatic allelic deletion or loss of heterozygosity (LOH) in a tumor is considered circumstantial evidence for the location of tumor suppressor genes. We have examined 27 primary epithelial ovarian tumors for the presence of LOH at 19 polymorphic markers on chromosomes 1, 5, 6, 9, 11, 13, and 17. Markers near the adenomatous polyposis coli (APC) gene at 5q21 showed LOH in 50% (10/20) of informative cases. LOH was seen in 53% (8/15) at the IFNA locus on 9p, another region implicated in other tumors, but not previously associated with ovarian cancer. We observed LOH for markers on 11p15 in 50% (12/24) of ovarian cancer DNAs from informative cases, while only 25% (4/16) at 11q13 and 29% (5/17) at 11q24 showed LOH. Only a portion of distal 11p was deleted in six cases. The incidence of LOH (50%) at HGH (17q22-q24) was greater than that at D17S579 (39%; 17q21), a locus tightly linked to BRCA1. Sixty-four percent (7/11) showed allelic loss at 17p11. LOH was infrequently observed at markers on chromosomes 1, 6, and 13q. Most cases showing LOH were stage III or IV, and most showed LOH at more than one locus. These studies support the concept that multiple genetic loci are involved in ovarian tumorigenesis. Two additional regions thought to harbor genes important in other cancers, 5q21 and 9p21, can now be added to the growing spectrum of molecular alterations seen in ovarian cancer.
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PMID:Molecular genetic changes associated with ovarian cancer. 795 92

In a study of nine families with "site-specific" ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age < 50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .32-1.0). If predisposition to both breast and ovarian cancer is assumed, the proportion linked is 1.0 (95% confidence interval .46-1.0). The linkage of familial site-specific ovarian cancer to BRCA1 indicates the possibility of predictive testing in such families; however, this is only appropriate in families where the evidence for linkage to BRCA1 is conclusive.
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PMID:Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. 797 46


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