FOUNDING BRCA1 MUTATIONS IN HEREDITARY BREAST AND OVARIAN-CANCER IN SOUTHERN SWEDEN

Nine different germ-line mutations in the BRCA1 breast and ovarian can cer susceptibility gene were identified in 15 of 47 kindreds from sout hern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predic ted to give rise to premature translation termination and include seve n frameshift insertions or deletions, a nonsense mutation, and a splic e acceptor site mutation. The remaining mutation is a missense mutatio n (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mu tations were identified: the nucleotide 2595 deletion A was found in f ive families, the C 1806 T nonsense mutation in three families, the 31 66 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 s upports common origins of the mutations. Eleven of the 15 kindreds man ifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 fam ilies in which no BRCA1 alterations were detected included 1 breast-ov arian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor ty pes found in BRCA1 mutation/haplotype carriers included prostatic, pan creas, skin, and lung cancer, a malignant melanoma, an oligodendroglio ma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P < .001). The present study confirms th e involvement of BRCA1 in disease predisposition for a subset of hered itary breast cancer families often characterized by ovarian cancers.