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

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          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.

          Author Summary

          Gene fusions represent an important class of cancer genes, created by rearrangements of the genome that bring together two different genes. Because they are unique to cancer cells, gene fusions are ideal diagnostic markers and therapeutic targets. While gene fusions were once thought restricted mainly to blood cancers, recent discoveries suggest they are more widespread. Here, we have developed an approach for mining DNA microarray data to detect the tell-tale signatures of gene fusions, as “breakpoints” occurring within the encoding DNA or expressed transcripts. We apply this approach to a large collection of nearly 1,000 human cancer specimens. From this analysis, we discover and verify twelve new gene fusions occurring in diverse cancer types. We verify that some of these rearrangements recur in other samples of the same cancer type (supporting a causal role) and that the cancers show dependency on the fusion for cancer cell growth. Notably, some of these fusions (e.g. CEP85L/ROS1 in angiosarcoma) represent the first for that cancer type and thus provide important new biological insight. Some are also good drug targets (including rearrangements of ROS1, RAF1, and CDK6 kinases), with clear implications for therapy.

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          Most cited references66

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          Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

          Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
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            Reorganizing the protein space at the Universal Protein Resource (UniProt)

            The mission of UniProt is to support biological research by providing a freely accessible, stable, comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase, with extensive cross-references and querying interfaces. UniProt is comprised of four major components, each optimized for different uses: the UniProt Archive, the UniProt Knowledgebase, the UniProt Reference Clusters and the UniProt Metagenomic and Environmental Sequence Database. A key development at UniProt is the provision of complete, reference and representative proteomes. UniProt is updated and distributed every 4 weeks and can be accessed online for searches or download at http://www.uniprot.org.
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              ROS1 rearrangements define a unique molecular class of lung cancers.

              Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                April 2013
                April 2013
                25 April 2013
                : 9
                : 4
                : e1003464
                Affiliations
                [1 ]Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America
                [2 ]Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
                [3 ]Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America
                [4 ]Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, United States of America
                University of Washington, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                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.

                Article
                PGENETICS-D-12-02993
                10.1371/journal.pgen.1003464
                3636093
                23637631
                1f3678c0-9969-4f69-a7ec-53cf0ee10fe9
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 December 2012
                : 5 March 2013
                Page count
                Pages: 19
                Funding
                This work was supported in part by grants from the National Institutes of Health (CA112016 to JRP, CA124832 and RC2CA14891 to AJW), California Breast Cancer Research Program (15IB-0123 to JRP), and Sarcoma Foundation of America (JRP). Fellowship support was provided by the Stanford Genome Training Program (CPG), National Science Foundation (AHS), Stanford Graduate Fellowship Program (AHS), Cancer Biology Training Program (AHS), Gates Millennium Scholarship Program (NC), CHRP Fellowship Program (JB), Harry Lyon Machen Fellowship Program (JB), Hyundai Fellowship Program (JB and JRP), and National Defense Science and Engineering Graduate Research Fellowship (CADV). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genomics
                Genome Analysis Tools
                Genome Scans
                Genome Expression Analysis
                Medicine
                Oncology
                Cancers and Neoplasms
                Breast Tumors
                Bone and Soft Tissue Sarcomas
                Gastrointestinal Tumors
                Hematologic Cancers and Related Disorders
                Skin Tumors
                Basic Cancer Research

                Genetics
                Genetics

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