title: 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: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Craig P
authors: CP
authors: Giacomini
authors: Steven
authors: S
authors: Sun
authors: Sushama
authors: S
authors: Varma
authors: A Hunter
authors: AH
authors: Shain
authors: Marilyn M
authors: MM
authors: Giacomini
authors: Jay
authors: J
authors: Balagtas
authors: Robert T
authors: RT
authors: Sweeney
authors: Everett
authors: E
authors: Lai
authors: Catherine A
authors: CA
authors: Del Vecchio
authors: Andrew D
authors: AD
authors: Forster
authors: Nicole
authors: N
authors: Clarke
authors: Kelli D
authors: KD
authors: Montgomery
authors: Shirley
authors: S
authors: Zhu
authors: Albert J
authors: AJ
authors: Wong
authors: Matt
authors: M
authors: van de Rijn
authors: Robert B
authors: RB
authors: West
authors: Jonathan R
authors: JR
authors: Pollack
mesh_terms: D050939:Gene Fusion; D023281:Genomics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases
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