Nature Genetics
11, 428 - 433 (1995)
doi:10.1038/ng1295-428
Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype−phenotype correlationSimon A. Gayther1, *, William Warren2, *, Sylvie Mazoyer1, *, Paul A. Russell1, Patricia A. Harrington1, Mathias Chiano1, 3, Sheila Seal2, Rifat Hamoudi2, Elizabeth J. van Rensburg1, 4, Alison M. Dunning1, Richard Love5, Gareth Evans6, Doug Easton7, David Clayton3, Michael R. Stratton2
& Bruce A.J. Ponder1
1CRC Human Cancer Genetics Research Group, Box 238, Addenbrooke's Hospital Hills Road, Cambridge, CB2 2QQ, UK
2Section of Molecular Carcinogenesis, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
3MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK
4Department of Human Genetics, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa
5Cancer Prevention Programme, 1300 University Avenue, 7C, Madison, Wisconsin 53706, USA
6Regional Genetics Service, St. Mary's Hospital Manchester, Whitworth Park, Manchester M13 OJH, UK
7Department of Community Medicine, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK
*These authors contributed equally to the study. Correspondence should be addressed to S.A.G. Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80−90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty−two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.
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