HIGH ALLELE LOSS RATES AT 17Q12-Q21 IN BREAST AND OVARIAN-TUMORS FROM BRCA1-LINKED FAMILIES

Loss of heterozygosity (LOH) was evaluated in 174 breast and ovarian tumors derived from 94 families with at least 3 first-degree relatives affected with either of these cancers. By linkage analysis 26 families were identified as having a high I posterior probability of being due to BRCA1 (the breast/ovarian cancer susceptibility locus on 17q12-21) with lod scores varying from 0.51 to 9.49. Tumor genotypes were determined at at least 2 constitutionally heterozygous markers flanking BRCA1 in a total of 58 tumors from these families. These tumors were derived from 52 patients, the BRCA1 mutation carrier status of which was evidenced by DNA sequencing in 20, and inferred by reconstructing haplotypes in the remainder. LOH was detected in 50 (86%) tumors, and invariably involved the wild-type allele. Where informative, this allele was of paternal origin in 33 cases and of maternal origin in 10 cases. These results strongly suggest that BRCA1 is a tumor suppressor gene and that LOH is greatly favored to fully inactivate it. (C) 1995 Wiley-Liss, Inc.