Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types

<div><p>Gene fusions, like <i>BCR/ABL1</i> 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 <i>ROS1</i> tyrosine kinase in angiosarcoma (<i>CEP85L/ROS1</i>), <i>SLC1A2</i> glutamate transporter in colon cancer (<i>APIP/SLC1A2</i>), <i>RAF1</i> kinase in pancreatic cancer (<i>ATG7/RAF1</i>) and anaplastic astrocytoma (<i>BCL6/RAF1</i>), <i>EWSR1</i> in melanoma (<i>EWSR1/CREM</i>), <i>CDK6</i> kinase in T-cell acute lymphoblastic leukemia (<i>FAM133B/CDK6</i>), and <i>CLTC</i> in breast cancer (<i>CLTC/VMP1</i>). 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 <i>EGFRvIII</i> and <i>FIP1L1/PDGFRA</i>. 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.</p>