WGS of Homo Sapiens: adult female breast
Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution especially in the genesis of amplicons. In a detailed reconstruction of events in chr17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic datasets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently co-amplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2 transfected human normal mammary epithelial cells. Co-amplification of other functionally tested oncogenic elements in other breast tumors examined such as RIPK2 and MYC (8q) also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer..
FUC_T58_GES14_00080_GCCAAT_AC3FLGACXX_ALL_001