Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation

摘要: BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, can be inactivated by multiple mechanisms and determining its status not trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions at least 10 Mb, were found robust indicator this setting. Two major ploidy-specific cutoffs LST distributions sufficient distinguish highly rearranged BLCs with 85% proven BRCA1-inactivated from less devoid cases. The was validated second independent series 55 primary 17 BLC-derived tumor cell lines. High numbers LSTs resembling observed 4 2 lines that harbored BRCA2 mutations. Overall, the predicted BRCA1/2 100% sensitivity 90% specificity (97% accuracy). This assay may ease challenge selecting patients for genetic testing or recruitment clinical trials novel emerging therapies target DNA repair deficiencies cancer.