LETTER TO JMG Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families

Identification of the BRCA1 and BRCA2 genes was a major advance in the understanding of the familial forms of breast cancer, as alterations of these genes result in a high predisposition to breast cancer. 2 To date, analysis of BRCA1 and BRCA2 coding sequences by mutation screening methods based on PCR sequencing protocols has allowed the identification of at least 900 different point or small disease causing germline alterations (Breast Cancer Information Core, BIC database). Furthermore, several large BRCA1 rearrangements have been reported, detected by Southern blotting, lymphocyte transcript analysis, or long range PCR. The majority of characterised rearrangements result from unequal recombination events between Alu sequences. We have estimated that the contribution of large rearrangements to the spectrum of BRCA1 mutations is close to 10% in French breast-ovarian cancer families. Only two rearrangements of the BRCA2 gene have been detected to date: a 5 kb deletion skipping exon 3 and a 6.2 kb deletion removing exons 12-13. 17 However, few groups have systematically looked for BRCA2 rearrangements in defined series of breast cancer cases. In order to detect such rearrangements, we have developed a bar code on combed DNA for the BRCA2 gene, which leads to a panoramic view of this gene and its flanking regions, as previously described for BRCA1. 21 We have concurrently used BRCA1 and BRCA2 bar codes to analyse a series of 26 highly selected French patients with a family history of breast cancer only, who were previously found to be negative for point or small mutations in both BRCA1 and BRCA2 genes.