THE MAJORITY OF 22 DUTCH HIGH-RISK BREAST-CANCER FAMILIES ARE DUE TO EITHER BRCA1 OR BRCA2

We have analyzed, by a combination of mutation and linkage analysis, t he genetic basis of 22 breast cancer families in which at least 4 case s of either breast cancer diagnosed under the age of 60 or ovarian can cer had occurred, Chain-terminating mutations in BRCA1 were evidenced in 6 families, and posterior probabilities of >0.90 of being linked to BRCA1 in 3, The breast versus ovarian cancer ratio in these 9 familie s was approximately 2:1. Among the remaining 13 families, significant linkage to markers flanking BRCA2 was established in the admixture tes t with a maximum multipoint lod score of 3.38, but there was no statis tical evidence for genetic heterogeneity. The breast:ovarian cancer ra tio in these families was 7:1, suggesting BRCA2 confers a much lower r isk for ovarian cancer than does BRCA1. These results suggest that BRC A2 will explain a significant proportion of hereditary breast cancer i n the Netherlands, and, together with BRCA1, account for the majority of all high-risk families.