PDF file - 2.35MB, Experimental set of 65 BLCs, Processing SNP-arrays, Inferring chromosome number, Detection of tumor ploidy, Breakpoints estimation, Validation of LSTs by Next Generation Sequencing and Sanger sequencing, Features of LSTs, Distribution of LSTs along the genome, LSTs in detection of BRCA1 tumors in Experimental and Validation sets, Somatic BRCA1 mutations detected in BLCs with high LST, BRCA2 mutations detected in BLCs with high LST, Triple negative cell lines, & Stability of LSTs in xenograft passages as compared to primary tumors.
ARTICLE ABSTRACTBRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). 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 single-nucleotide polymorphism 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 Res; 72(21); 5454–62. ©2012 AACR.