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

Abstract

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.

• Authors: Craig P Giacomini, Steven Sun, Sushama Varma, A Hunter Shain, Marilyn M Giacomini, Jay Balagtas, Robert T Sweeney, Everett Lai, Catherine A Del Vecchio, Andrew D Forster, Nicole Clarke, Kelli D Montgomery, Shirley Zhu, Albert J Wong, Matt van de Rijn, Robert B West, Jonathan R Pollack
• Journal: PLoS genetics (PLoS Genet) Vol. 9 Issue 4 Pg. e1003464 (Apr 2013) ISSN: 1553-7404 [Electronic] United States
• PMID: 23637631 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Oncogene Proteins, Fusion
• Proto-Oncogene Proteins
• Protein-Tyrosine Kinases

Topics

• Gene Fusion
• Genomics
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics)
• Oncogene Proteins, Fusion (genetics)
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)