A HIGH-INCIDENCE OF BRCA1 MUTATIONS IN 20 BREAST-OVARIAN CANCER FAMILIES

We have analyzed 20 breast-ovarian cancer families, the majority of wh ich show positive evidence of linkage to chromosome 17q12, for germ-li ne mutations in the BRCA1 gene. BRCA1 mutations cosegregating with bre ast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mu tations have not been reported previously. The majority of mutations w ere found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2%-88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DN A led to the identification of a mutation in the coding region of BRCA 1 in 12 families, and cDNA analysis revealed an abnormal or missing BR CA1 transcript in 4 of the 8 remaining families. A total of eight muta tions were associated with a reduced quantity of BRCA1 transcript. We were unable to detect BRCA1 mutations in 4 of the 20 families, but onl y 1 of these was clearly linked to BRCA1. Ir is expected that the majo rity of clear examples of the breast-ovarian cancer syndrome will be a ssociated with germ-line mutations in the coding region of BRCA1.