An integrative approach to reveal driver gene fusions from paired-end sequencing data in cancer.
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.
Wang
Xiao-Song
XS
Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA.
Prensner
John R
JR
Chen
Guoan
G
Cao
Qi
Q
Han
Bo
B
Dhanasekaran
Saravana M
SM
Ponnala
Rakesh
R
Cao
Xuhong
X
Varambally
Sooryanarayana
S
Thomas
Dafydd G
DG
Giordano
Thomas J
TJ
Beer
David G
DG
Palanisamy
Nallasivam
N
Sartor
Maureen A
MA
Omenn
Gilbert S
GS
Chinnaiyan
Arul M
AM
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