Analysis abstract
Nature Biotechnology 27, 1005 - 1011 (2009)
Published online: 1 November 2009 | doi:10.1038/nbt.1584
An integrative approach to reveal driver gene fusions from paired-end sequencing data in cancer
Xiao-Song Wang1,2,3, John R Prensner1,3,8, Guoan Chen4,8, Qi Cao1,3, Bo Han1,3, Saravana M Dhanasekaran1,3, Rakesh Ponnala1, Xuhong Cao1,3, Sooryanarayana Varambally1,3,5, Dafydd G Thomas3, Thomas J Giordano3, David G Beer4, Nallasivam Palanisamy1,3, Maureen A Sartor2, Gilbert S Omenn2 & Arul M Chinnaiyan1,2,3,5,6,7
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.
- Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA.
- National Center for Integrative Biomedical Informatics, CCMB, Ann Arbor, Michigan, USA.
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
- Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
- Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA.
- Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
- These authors contributed equally to this work.
Correspondence to: Gilbert S Omenn2 e-mail: gomenn@umich.edu
Correspondence to: Arul M Chinnaiyan1,2,3,5,6,7 e-mail: arul@umich.edu
