title: Systems consequences of amplicon formation in human breast cancer.
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.
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA;
authors.forename: Koichiro
authors.initials: K
authors.lastname: Inaki
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA;
authors.forename: Francesca
authors.initials: F
authors.lastname: Menghi
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Xing Yi
authors.initials: XY
authors.lastname: Woo
authors.affiliation: 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;
authors.forename: Joel P
authors.initials: JP
authors.lastname: Wagner
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada;
authors.forename: Pierre-Étienne
authors.initials: PÉ
authors.lastname: Jacques
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Yi Fang
authors.initials: YF
authors.lastname: Lee
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA;
authors.forename: Phung Trang
authors.initials: PT
authors.lastname: Shreckengast
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Wendy WeiJia
authors.initials: WW
authors.lastname: Soon
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA;
authors.forename: Ankit
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Audrey S M
authors.initials: AS
authors.lastname: Teo
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Alexis Jiaying
authors.initials: AJ
authors.lastname: Khng
authors.affiliation: Genome Technology and Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Swee Hoe
authors.initials: SH
authors.lastname: Ong
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Denis
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
authors.forename: Niranjan
authors.initials: N
authors.lastname: Nagarajan
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore; The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
authors.forename: R Krishna Murthy
authors.initials: RK
authors.lastname: Karuturi
authors.affiliation: National Institute of Genomic Medicine, Periferico Sur 4124, Mexico City 01900, Mexico.
authors.forename: Alfredo Hidalgo
authors.initials: AH
authors.lastname: Miranda
authors.affiliation: 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.
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D020440:Gene Duplication; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D019313:BRCA1 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C492913:BRCA1 protein, human; C508053:ERBB2 protein, human