title: Gene fusions associated with recurrent amplicons represent a class of passenger aberrations in breast cancer.
abstract: Application of high-throughput transcriptome sequencing has spurred highly sensitive detection and discovery of gene fusions in cancer, but distinguishing potentially oncogenic fusions from random, "passenger" aberrations has proven challenging. Here we examine a distinctive group of gene fusions that involve genes present in the loci of chromosomal amplifications--a class of oncogenic aberrations that are widely prevalent in breast cancers. Integrative analysis of a panel of 14 breast cancer cell lines comparing gene fusions discovered by high-throughput transcriptome sequencing and genome-wide copy number aberrations assessed by array comparative genomic hybridization, led to the identification of 77 gene fusions, of which more than 60% were localized to amplicons including 17q12, 17q23, 20q13, chr8q, and others. Many of these fusions appeared to be recurrent or involved highly expressed oncogenic drivers, frequently fused with multiple different partners, but sometimes displaying loss of functional domains. As illustrative examples of the "amplicon-associated" gene fusions, we examined here a recurrent gene fusion involving the mediator of mammalian target of rapamycin signaling, RPS6KB1 kinase in BT-474, and the therapeutically important receptor tyrosine kinase EGFR in MDA-MB-468 breast cancer cell line. These gene fusions comprise a minor allelic fraction relative to the highly expressed full-length transcripts and encode chimera lacking the kinase domains, which do not impart dependence on the respective cells. Our study suggests that amplicon-associated gene fusions in breast cancer primarily represent a by-product of chromosomal amplifications, which constitutes a subset of passenger aberrations and should be factored accordingly during prioritization of gene fusion candidates.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA.
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.forename: Sunita
authors.initials: S
authors.lastname: Shankar
authors.forename: Scott
authors.initials: S
authors.lastname: Deroo
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Iyer
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar-Sinha
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D050939:Gene Fusion; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1