Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types

Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a "b...

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Published inPLoS genetics Vol. 9; no. 4; p. e1003464
Main Authors Giacomini, Craig P, Sun, Steven, Varma, Sushama, Shain, A Hunter, Giacomini, Marilyn M, Balagtas, Jay, Sweeney, Robert T, Lai, Everett, Del Vecchio, Catherine A, Forster, Andrew D, Clarke, Nicole, Montgomery, Kelli D, Zhu, Shirley, Wong, Albert J, van de Rijn, Matt, West, Robert B, Pollack, Jonathan R
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.04.2013
Public Library of Science (PLoS)
Subjects
Biology
Breast cancer
Cancer
Colorectal cancer
Deoxyribonucleic acid
DNA
Gene Fusion
Genes
Genetic aspects
Genetic transcription
Genomes
Genomics
Humans
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Medical research
Medicine
Melanoma
Oncogene Proteins, Fusion - genetics
Physiology, Pathological
Prostate cancer
Protein-Tyrosine Kinases - genetics
Proteins
Proto-Oncogene Proteins - genetics
Stomach cancer
United States
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Summary:Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a "breakpoint analysis" pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1). Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases), with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis.
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Conceived and designed the experiments: CPG JRP. Performed the experiments: CPG SV AHS MMG JB RTS CADV ADF NC KDM SZ. Analyzed the data: CPG SS SV AHS MMG JB RTS EL CADV ADF SZ AJW RBW JRP. Contributed reagents/materials/analysis tools: CPG AJW MvdR RBW JRP. Wrote the paper: CPG JRP.
The authors have declared that no competing interests exist.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003464