A sporadic breast tumor with a somatically acquired complex genomic rearrangement in BRCA1

Germ-line mutations in BRCA1 cause a substantial proportion of inherited br east cancer, and most result in inactivated BRCA1 I proteins upon translati on. Tumours developing in BRCA1 mutation carriers generally show loss of th e wild-type allele. However, acquired inactivating mutations in BRCA1 in no n-inherited breast tumours showing loss of heterozygosity at the gene locus have not been detected so far. Here we provide evidence that such mutation s can be detected in a small proportion of breast tumours, Prompted by rece nt reports of Alu-mediated large genomic rearrangements in BRCA1, we have i nvestigated whether such rearrangements might occur in sporadic breast canc er as well and have been missed thus far by traditional PCR-based mutation screening technology. To this end, we performed Southern blot analysis of 8 1 apparently sporadic breast tumours using probes covering exons 6-24 and 3 restriction enzymes. We identified case with an acquired rearrangement (1. 2%), indicating that BRCA1 inactivation through changes in the primary geno mic sequence of the gene is uncommon in breast cancer. (C) 2000 Wiley-Liss, Inc.