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• W2588698825 abstract "Breast cancer is the most common cancer among women in the United Kingdom, currently affecting one in twelve; the frequency varies quite markedly between countries, affecting one in nine in the United States but only one in sixty in Japan. Each year there are approximately 30000 new cases in the United Kingdom. Although most breast cancer is thought to be sporadic, about 6% of cases are estimated to be familial. This means that one in 200 women gets breast cancer as a result of an inherited mutation in a susceptibility gene. A small fraction of these cases is caused by germline mutations in the p53 and ataxia telangiectasia genes. Four years ago, the first major breast cancer susceptibility gene, BRCA1, was mapped to human chromosome 17 [1]. An international collaboration, involving the study of over 200 affected families, showed that the BRCA 1 gene is implicated in almost all families in which there is an inherited susceptibility to both female breast and ovarian cancer [2]. However, less than half the families showing multiple cases of just breast cancer showed linkage to BRCA1. And it has recently been found that families with inherited susceptibility to both male and female breast cancer, do not show linkage to BRCA1 [3]. Women carrying a BRCA 1 mutation have a lifetime risk of breast or ovarian cancer of over 90%. Genetic mapping studies placed the BRCA1 gene between the polymorphic markers D17S702 and D17S78. This is a region of about one million base pairs, harbouring approximately thirty genes. Studies of allele loss in tumours from affected family members indicated that BRCA1 is a tumour suppressor gene: thus, the inherited mutation is thought to inactivate one copy of the gene, but for tumours to develop, the second, wildtype copy has also to be lost [4]. For the past four years, many groups have been engaged in a race to clone BRCA 1 by 'positional cloning' - that is, cloning guided by the gene's chromosomal map position. This goal has finally been achieved by Roger Wiseman's group at the National Institute of Environmental Health Sciences in collaboration with Mark Skolnick's group at the University of Utah and Myriad Genetics, Inc. [5,6]. The BRCA 1 gene has been found to encompass over 100 kilobases (kb) of DNA, and to map in the middle of the region defined by genetic mapping. The BRCA 1 gene encodes a pre-RNA with 21 exons, which are spliced together to make a 7.8 kb messenger RNA that is expressed in several tissues, including breast and ovary. The mRNA sequence has a large open reading frame encoding a 1 863 residue protein. The product of the BRCA 1 gene is predicted to be a transcription factor, as its amino-terminal region contains a zinc-finger domain similar to those found in many DNA-binding proteins. The rest of the sequence is very acidic, but shows no significant homologies to any known protein. The evidence identifying the cloned gene as BRCA I1 depends on the presence of germline mutations in large breast-ovarian cancer families but not the general population. Four such mutations have been found. One is a missense mutation, found in an African-American family, that causes the non-conservative substitution of a methionine residue by arginine. The other three families have clear loss-of-function mutations: one is a nonsense mutation, changing a glutamine codon to a stop codon; another is a frameshift mutation, an insertion that changes the frame in which the downstream sequence is read; and in the third family, the disease-linked copy of BRCA 1 is not expressed, presumably as a result of some, as yet unidentified, promoter mutation. Genes that are responsible for familial susceptibility to cancer are usually also altered in sporadic forms of the same diseases. For example, although germline mutations of the APC gene on chromosome 5 are responsible for less than 1 % of colon cancer cases, somatic mutations of the APC gene are thought to occur in all colon tumours. The cloning of BRCA 1 has allowed its role in sporadic and breast cancer to be investigated [6]. Thirty-two early-onset breast tumours and twelve ovarian tumours, all showing allele loss in the BRCA 1 region, were tested for BRCA 1 mutations: three of the breast tumours were found to have BRCA 1 mutations (one nonsense and two missense), and one ovarian tumour was found to have a missense mutation. In each case, the mutation was found also to be present in DNA from normal tissues of the patients, showing that they were all germline mutations. Two of the four cases were subsequently found to have family histories of breast and ovarian cancer - one was an AfricanAmerican woman who had the same methionine-toarginine substitution that, as explained above, was found in an apparently unrelated family, suggesting that this may be a common predisposing mutation in African" @default.
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• W2588698825 date "1994-01-01" @default.
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• W2588698825 title "BRCA 1 down, BRCA2 to go The breast cancer susceptibility gene BRCA1 has been cloned and a second susceptibility gene, BRCA2, chromosomally mapped; will most breast and ovarian cancer turn out to be familial?" @default.
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