Both authors contributed equally to this work.
A diagnostic genetic test for the physical mapping of germline rearrangements in the susceptibility breast cancer genes BRCA1 and BRCA2†
Article first published online: 4 APR 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Focus on CNV Detection with Diagnostic Arrays
Volume 33, Issue 6, pages 998–1009, June 2012
How to Cite
Cheeseman, K., Rouleau, E., Vannier, A., Thomas, A., Briaux, A., Lefol, C., Walrafen, P., Bensimon, A., Lidereau, R., Conseiller, E. and Ceppi, M. (2012), A diagnostic genetic test for the physical mapping of germline rearrangements in the susceptibility breast cancer genes BRCA1 and BRCA2. Hum. Mutat., 33: 998–1009. doi: 10.1002/humu.22060
Communicated David E. Goldgar
- Issue published online: 7 MAY 2012
- Article first published online: 4 APR 2012
- Accepted manuscript online: 21 FEB 2012 12:17PM EST
- Manuscript Accepted: 3 FEB 2012
- Manuscript Received: 29 AUG 2011
- breast cancer;
- Genomic Morse Code;
- molecular combing
The BRCA1 and BRCA2 genes are involved in breast and ovarian cancer susceptibility. About 2 to 4% of breast cancer patients with positive family history, negative for point mutations, can be expected to carry large rearrangements in one of these two genes. We developed a novel diagnostic genetic test for the physical mapping of large rearrangements, based on molecular combing (MC), a FISH-based technique for direct visualization of single DNA molecules at high resolution. We designed specific Genomic Morse Codes (GMCs), covering the exons, the noncoding regions, and large genomic portions flanking both genes. We validated our approach by testing 10 index cases with positive family history of breast cancer and 50 negative controls. Large rearrangements, corresponding to deletions and duplications with sizes ranging from 3 to 40 kb, were detected and characterized on both genes, including four novel mutations. The nature of all the identified mutations was confirmed by high-resolution array comparative genomic hybridization (aCGH) and breakpoints characterized by sequencing. The developed GMCs allowed to localize several tandem repeat duplications on both genes. We propose the developed genetic test as a valuable tool to screen large rearrangements in BRCA1 and BRCA2 to be combined in clinical settings with an assay capable of detecting small mutations. Hum Mutat 33:998–1009, 2012. © 2012 Wiley Periodicals, Inc.