Nature Genetics
15, 103 - 105 (1997)
doi:10.1038/ng0197-103
Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 geneSimon A. Gayther*, 1, Jonathon Mangion*, 2, Paul Russell1, Sheila Seal2, Rita Barfoot2, Bruce A.J. Ponder1, Michael R. Stratton2
& Douglas Easton3
1CRC Human Cancer Genetics Research Group, Box 238, Addenbrooke's Hospital, Hills Road, Cambridge, CB22QQ, UK.
2Section of Molecular Carcinogenesis, Institute of Cancer Research, Haddow Laboratories, 15 CotswoldRoad, Button, Surrey, SM25NG, UK.
3CRC Genetic Epidemiology Group, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 2SR UK.
*S.A. G. & J.M. contributed equally to the study. The breast cancer susceptibility gene BRCA2 on chromosome 13q12−13 has recently been identified1. 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 cancer2−4. 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 cancer6. 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 mutation7,8. 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 0/?CA2-linked families provide support for this correlation.
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