title: An integrative approach to reveal driver gene fusions from paired-end sequencing data in cancer.
abstract: Cancer genomes contain many aberrant gene fusions-a few that drive disease and many more that are nonspecific passengers. We developed an algorithm (the concept signature or 'ConSig' score) that nominates biologically important fusions from high-throughput data by assessing their association with 'molecular concepts' characteristic of cancer genes, including molecular interactions, pathways and functional annotations. Copy number data supported candidate fusions and suggested a breakpoint principle for intragenic copy number aberrations in fusion partners. By analyzing lung cancer transcriptome sequencing and genomic data, we identified a novel R3HDM2-NFE2 fusion in the H1792 cell line. Lung tissue microarrays revealed 2 of 76 lung cancer patients with genomic rearrangement at the NFE2 locus, suggesting recurrence. Knockdown of NFE2 decreased proliferation and invasion of H1792 cells. Together, these results present a systematic analysis of gene fusions in cancer and describe key characteristics that assist in new fusion discovery.
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.forename: Rakesh
authors.initials: R
authors.lastname: Ponnala
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.forename: Gilbert S
authors.initials: GS
authors.lastname: Omenn
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000465:Algorithms; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D050939:Gene Fusion / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA