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Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

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Published OnlineFirst April 1, 2020; DOI: 10.1158/2159-8290.CD-19-1030 RESEARCH ARTICLE Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes Matthew Clarke1, Alan Mackay1, Britta Ismer2,3,4, Jessica C. Pickles5, Ruth G. Tatevossian6, Scott Newman7, Tejus A. Bale8, Iris Stoler9, Elisa Izquierdo1, Sara Temelso1, Diana M. Carvalho1, Valeria Molinari1, Anna Burford1, Louise Howell1, Alex Virasami5, Amy R. Fairchild5, Aimee Avery5, Jane Chalker5, Mark Kristiansen5, Kelly Haupfear6, James D. Dalton6, Wilda Orisme6, Ji Wen6, Michael Hubank10, Kathreena M. Kurian11, Catherine Rowe11, Mellissa Maybury12,13,14, Stephen Crosier15, Jeffrey Knipstein16, Ulrich Schüller17,18, Uwe Kordes18, David E. Kram19, Matija Snuderl20, Leslie Bridges21, Andrew J. Martin22, Lawrence J. Doey23, Safa Al-Sarraj23, Christopher Chandler24, Bassel Zebian24, Claire Cairns24, Rachael Natrajan25, Jessica K.R. Boult26, Simon P. Robinson26, Martin Sill2, Ira J. Dunkel27, Stephen W. Gilheeney27, Marc K. Rosenblum8, Debbie Hughes10, Paula Z. Proszek10, Tobey J. Macdonald28, Matthias Preusser29, Christine Haberler29,30, Irene Slavc31, Roger Packer32, Ho-Keung Ng33, Shani Caspi34, Mara Popović35, Barbara Faganel Kotnik36, Matthew D. Wood37, Lissa Baird38, Monika Ashok Davare39, David A. Solomon40,41, Thale Kristin Olsen42, Petter Brandal43, Michael Farrell44, Jane B. Cryan44, Michael Capra45, Michael Karremann46, Jens Schittenhelm47, Martin U. Schuhmann48, Martin Ebinger49, Winand N.M. Dinjens50, Kornelius Kerl51, Simone Hettmer52, Torsten Pietsch53, Felipe Andreiuolo53, Pablo Hernáiz Driever54, Andrey Korshunov55, Lotte Hiddingh2, Barbara C. Worst2,4,56, Dominik Sturm2,4,56, Marc Zuckermann2,4, Olaf Witt2,4,56, Tabitha Bloom57, Clare Mitchell57, Evelina Miele58, Giovanna Stefania Colafati59, Francesca Diomedi-Camassei60, Simon Bailey15, Andrew S. Moore12,13,14, Timothy E.G. Hassall13,61,62, Stephen P. Lowis11, Maria Tsoli63,64, Mark J. Cowley63,64, David S. Ziegler63,64, Matthias A. Karajannis27, Kristian Aquilina65, Darren R. Hargrave66, Fernando Carceller67,68, Lynley V. Marshall67,68, Andreas von Deimling55,69, Christof M. Kramm70, Stefan M. Pfister2,4,56, Felix Sahm54,69, Suzanne J. Baker71, Angela Mastronuzzi72, Andrea Carai73, Maria Vinci58, David Capper9,74, Sergey Popov1,75, David W. Ellison6, Thomas S. Jacques5, David T.W. Jones2,4, and Chris Jones1 1Division of Molecular Pathology, Institute of Cancer Research, London, College Hospital NHS Trust, London, United Kingdom. 24Department of Neu- United Kingdom. 2German Cancer Research Center (DKFZ), Heidelberg, rosurgery, Kings College Hospital NHS Trust, London, United Kingdom. 25The Germany. 3Faculty of Biosciences, Heidelberg University, Heidelberg, Ger- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer many. 4Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Ger- Research, London, United Kingdom. 26Division of Radiotherapy and Imag- many. 5UCL Great Ormond Street Institute of Child Health, London, United ing, The Institute of Cancer Research, London, United Kingdom. 27Depart- Kingdom. 6Department of Neuropathology, St. Jude Children’s Research ment of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New Hospital, Memphis, Tennessee. 7Department of Computational Biology, St. York. 28Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Jude Children’s Research Hospital, Memphis, Tennessee. 8Department of Emory University School of Medicine, Atlanta, Georgia. 29Comprehensive Neuropathology, Memorial Sloan-Kettering Cancer Center, New York, New Cancer Center, Medical University of Vienna, Vienna, Austria. 30Institute of York. 9Charité Universitätsmedizin Berlin, corporate member of Freie Uni- Neurology, Medical University of Vienna, Vienna, Austria. 31Department of versität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Department of Neuropathology, Berlin, Germany. 10Molecular Diagnostics, Austria. 32Center for Neuroscience and Behavioural Medicine, Children’s Royal Marsden Hospital NHS Trust, Sutton, United Kingdom. 11Brain Tumour National Medical Center, Washington, DC. 33Department of Anatomical and Research Centre, University of Bristol, Bristol, United Kingdom. 12The Uni- Cellular Pathology, The Chinese University of Hong Kong, China. 34Cancer versity of Queensland Diamantina Institute, The University of Queensland, Research Center, Sheba Medical Center, Tel Aviv, Israel. 35Faculty of Medi- Woolloongabba, Australia. 13Oncology Service, Queensland Children’s Hos- cine, University of Ljubljana, Ljubljana, Slovenia. 36Department of Hema- pital, Brisbane, Australia. 14Child Health Research Centre, The University of tology and Oncology, University Children’s Hospital, Ljubljana, Slovenia. Queensland, South Brisbane, Australia. 15Newcastle Hospitals NHS Foun- 37Department of Pathology, Oregon Health & Science University, Portland, dation Trust, Newcastle, United Kingdom. 16Division of Pediatric Hematol- Oregon. 38Department of Neurosurgery, Oregon Health & Science Univer- ogy/Oncology/BMT, Medical College of Wisconsin, Milwaukee, Wisconsin. sity, Portland, Oregon. 39Department of Pediatrics, Oregon Health & Sci- 17Department of Neuropathology, University Hospital Hamburg-Eppendorf, ence University, Portland, Oregon. 40Department of Pathology, University and Research Institute Children’s Cancer Center, Hamburg, Germany. 18Pedi- of California, San Francisco, California. 41Clinical Cancer Genomics Labora- atric Hematology and Oncology, University Hospital Hamburg-Eppendorf, tory, University of California, San Francisco, California. 42Department of Hamburg, Germany. 19Section of Pediatric Hematology-Oncology, Wake Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden. Forest School of Medicine, Winston-Salem, North Carolina. 20Department 43Department of Oncology, Oslo University Hospital, Oslo, Norway. 44Depart- of Neuropathology, NYU Langone Health, New York, New York. 21Depart- ment of Histopathology, Beaumont Hospital, Dublin, Ireland. 45Paediatric ment of Neuropathology, St George’s Hospital NHS Trust, London, United Oncology, Our Lady’s Children’s Hospital, Dublin, Ireland. 46Department of Kingdom. 22Department of Neurosurgery, St George’s Hospital NHS Trust, Pediatrics, University Medical Center Mannheim, Medical Faculty Mannheim, London, United Kingdom. 23Department of Clinical Neuropathology, Kings Heidelberg University, Mannheim, Germany. 47Institute of Pathology and OF1 | CANCER DISCOVERY JULY 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst April 1, 2020; DOI: 10.1158/2159-8290.CD-19-1030 Neuropathology, University Hospital Tübingen, Germany. 48Department of Cancer Research Center (DKFZ), Heidelberg, Germany. 70Division of Pediatric Neurosurgery, University Hospital Tübingen, Germany. 49Department of Hematology and Oncology, University Medical Centre Göttingen, Germany. Pediatric Hematology and Oncology, University Hospital Tübingen, Germany. 71Department of Neurobiology, St. Jude Children’s Research Hospital, Mem- 50Department of Pathology, Erasmus Medical Center, Rotterdam, the Neth- phis, Tennessee. 72Neuro-oncology Unit, Department of Onco-haematology, erlands. 51Department of Pediatric Hematology and Oncology, University Cell and Gene Therapy, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy. Hospital Muenster, Germany. 52Department of Pediatric Hematology and 73Oncological Neurosurgery Unit, Department of Neuroscience and Neurore- Oncology, University Hospital Freiburg, Germany. 53Institute of Neuropathol- habilitation, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy. 74German ogy, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Bonn, Germany. 54Department of Paediatric Haematology/Oncology Charité Center (DKFZ), Heidelberg, Germany. 75Department of Pathology, University Universitätsmedizin, Berlin, Germany. 55Department of Neuropathology, Uni- of Wales Hospital NHS Trust, Cardiff, United Kingdom. 56 versity Hospital Heidelberg, Germany. Department of Pediatric Oncology, Note: Supplementary data for this article are available at Cancer Discovery Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Online (http://cancerdiscovery.aacrjournals.org/). Heidelberg, Germany. 57BRAIN UK, University of Southampton, Southamp- ton, United Kingdom. 58Department of Onco-haematology, Cell and Gene M. Clarke, A. Mackay, and B. Ismer contributed equally to this article. Therapy, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy. 59Oncological Corresponding Authors: Chris Jones, The Institute of Cancer Research, Neuroradiology Unit, Department of Diagnostic Imaging, Bambino Gesù Chil- 15 Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, United Kingdom. dren’s Hospital-IRCCS, Rome, Italy. 60Department of Laboratories - Pathol- Phone: 4420-872-24416; Fax: 4420-8722-4321; E-mail: chris.jones@icr. ogy Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy. 61Institute ac.uk; David T.W. Jones, Hopp Children’s Cancer Center Heidelberg (KiTZ) for Molecular Bioscience, The University of Queensland, St Lucia, Australia. and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 62School of Biomedical Sciences, Faculty of Health, Queensland
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  • Crystal Structure of EML1 Reveals the Basis for Hsp90 Dependence of Oncogenic EML4-ALK by Disruption of an Atypical Β-Propeller Domain

    Crystal Structure of EML1 Reveals the Basis for Hsp90 Dependence of Oncogenic EML4-ALK by Disruption of an Atypical Β-Propeller Domain

    Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain Mark W. Richardsa, Edward W. P. Lawb,La’Verne P. Rennallsc, Sara Busaccab, Laura O’Regana, Andrew M. Frya, Dean A. Fennellb, and Richard Baylissa,1 aDepartment of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom; bDepartment of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom; and cSection of Structural Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom Edited by Charles David Stout, The Scripps Research Institute, La Jolla, CA, and accepted by the Editorial Board February 24, 2014 (received for review December 9, 2013) Proteins of the echinoderm microtubule-associated protein (EMAP)- variant 1 and regression in some EML4-ALK–positive tumor like (EML) family contribute to formation of the mitotic spindle and models (7, 9, 10). Furthermore, clinical efficacy of an Hsp90 in- interphase microtubule network. They contain a unique hydropho- hibitor in EML4-ALK NSCLC has been confirmed (11), and bic EML protein (HELP) motif and a variable number of WD40 clinical trials are ongoing. However, because neither ALK nor repeats. Recurrent gene rearrangements in nonsmall cell lung cancer EML4 are native Hsp90 clients, it was proposed that Hsp90 sen- fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression sitivity of EML4-ALK fusions was due to their protein-folding of several fusion oncoprotein variants. We have determined a 2.6-Å properties, which might expose hydrophobic residues that lead to crystal structure of the representative ∼70-kDa core of EML1, re- Hsp90 recruitment (12).
  • S12967-021-02982-4.Pdf

    S12967-021-02982-4.Pdf

    Xia et al. J Transl Med (2021) 19:308 https://doi.org/10.1186/s12967-021-02982-4 Journal of Translational Medicine RESEARCH Open Access Molecular characteristics and clinical outcomes of complex ALK rearrangements identifed by next-generation sequencing in non-small cell lung cancers Peiyi Xia1†, Lan Zhang1†, Pan Li1†, Enjie Liu1, Wencai Li1, Jianying Zhang2, Hui Li3, Xiaoxing Su3 and Guozhong Jiang1* Abstract Background: Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next- generation sequencing (NGS). We investigated the characteristics of complex ALK rearrangements in non-small cell lung cancers using multiple molecular tests. Methods: Samples of non-small cell lung cancer patients were analyzed by targeted-capture DNA-based NGS with probes tilling the selected intronic regions of fusion partner genes, RNA-based NGS, RT-PCR, immunohistochemistry (IHC) and fuorescence in situ hybridization (FISH). Results: In a large cohort of 6576 non-small cell lung cancer patients, 343 (5.2%) cases harboring ALK rearrange- ments were identifed. Fourteen cases with complex ALK rearrangements were identifed by DNA-based NGS and classifed into three types by integrating various genomic features, including intergenic (n 3), intragenic (n 5) and “bridge joint” rearrangements (n 6). All thirteen cases with sufcient samples actually expressed= canonical EML4-ALK= fusion transcripts confrmed by RNA-based= NGS. Besides, positive ALK IHC was detected in 13 of 13 cases, and 9 of 11 cases were positive in FISH testing. Patients with complex ALK rearrangements who received ALK inhibitors treatment (n 6), showed no diference in progression-free survival (PFS) compared with patients with canonical ALK fusions n = 36, P 0.9291).