VARIATION OF RISKS OF BREAST AND OVARIAN-CANCER ASSOCIATED WITH DIFFERENT GERMLINE MUTATIONS OF THE BRCA2 GENE

The breast cancer susceptibility gene BRCA2 on chromosome 13q12-13 has recently been identified(1). Germline mutations of BRCA2 are predicte d to account for approximately 35% of families with multiple case, ear ly onset female breast cancer, and they are also associated with an in creased risk of male breast cancer, ovarian cancer, prostate cancer an d pancreatic cancer(2-4). Germline mutations of a second cancer suscep tibility gene BRCA1 (ref. 5), are associated with a strong predisposit ion to ovarian cancer as well as female breast cancer(6). Recent studi es 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(7,8). To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have a nalysed the distribution of mutations in 25 families with multiple cas es of breast and/or ovarian cancer ascertained in the United Kingdom a nd fire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Ana lysis of the mutation distribution along the length of the gene indica tes a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breas t 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 famil ies provide support for this correlation.