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Genome Res. 2014 Oct;24(10):1559-71. doi: 10.1101/gr.164871.113. Epub 2014 Sep 3.

Systems consequences of amplicon formation in human breast cancer.

Author information

1
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA;
2
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
3
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
4
Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada;
5
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA;
6
Genome Technology and Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
7
Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
8
Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
9
National Institute of Genomic Medicine, Periferico Sur 4124, Mexico City 01900, Mexico.
10
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA; The Jackson Laboratory, Bar Harbor, Maine 04609, USA; Edison.Liu@JAX.org.

Abstract

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 on chromosome 17, 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 data sets 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 coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, 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.

PMID:
25186909
PMCID:
PMC4199368
DOI:
10.1101/gr.164871.113
[Indexed for MEDLINE]
Free PMC Article

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