Chromosome as oncogenic organizer: functional consequences of focal amplification shaped by structural mutations in breast cancer. Homo sapiens

Chromosomal structural mutations play an important role in determining the transcriptional landscape of human breast cancers. We determined that pro-oncogenic and anti-oncogenic genes are clustered throughout the genome and that these clusters coincide with regions of segmental amplification and deletion. We constructed detailed structural mutation maps of representative breast cancers and found that tandem duplications appear to nucleate regions for amplification. Subsequent rearrangements link distant pro-oncogenic elements for co-amplification, and are associated with loss of tumor suppressors. We show that genes engaged in co-amplifications or conjoint deletions on 17q and 8q have pro-growth effects that are additive in nature. Our results suggest structural mutations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously.