Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation
Menée initialement sur 65 cas de carcinome du sein "basal-like", puis validée sur 55 cas complémentaires et 17 lignées cellulaires, cette étude identifie une signature génomique permettant de prédire l'inactivation de BRCA1/2
BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLCs). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using SNP-arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST) defined as chromosomal break between adjacent regions of at least 10 Mb were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.
Cancer Research , résumé, 2012