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Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding

  1. Author:
    Lee, Olivia W
    Rodrigues, Calvin
    Lin, Shu-Hong
    Luo,Wen
    Jones,Kristine
    Brown, Derek W
    Zhou,Weiyin
    Karlins, Eric
    Khan, Sairah M
    Baulande, Sylvain
    Raynal, Virginie
    Surdez, Didier
    Reynaud, Stephanie
    Rubio, Rebeca Alba
    Zaidi, Sakina
    Grossetête, Sandrine
    Ballet, Stelly
    Lapouble, Eve
    Laurence, Valérie
    Pierron, Gaelle
    Gaspar, Nathalie
    Corradini, Nadège
    Marec-Bérard, Perrine
    Rothman, Nathaniel
    Dagnall, Casey L
    Burdett, Laurie
    Manning, Michelle
    Wyatt, Kathleen
    Yeager, Meredith
    Chari,Raj
    Leisenring, Wendy M
    Kulozik, Andreas E
    Kriebel, Jennifer
    Meitinger, Thomas
    Strauch, Konstantin
    Kirchner, Thomas
    Dirksen, Uta
    Mirabello, Lisa
    Tucker, Margaret A
    Tirode, Franck
    Armstrong, Gregory T
    Bhatia, Smita
    Robison, Leslie L
    Yasui, Yutaka
    Romero-Pérez, Laura
    Hartmann, Wolfgang
    Metzler, Markus
    Diver, W Ryan
    Lori, Adriana
    Freedman, Neal D
    Hoover, Robert N
    Morton, Lindsay M
    Chanock, Stephen J
    Grünewald, Thomas G P
    Delattre, Olivier
    Machiela, Mitchell J

  2. Author Address

    1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 2Inserm U830, PSL Université, Research Center, Institut Curie, 75005 Paris, France; SIREDO Oncology Centre, Institut Curie, 75005 Paris, France. 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA. 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Frederick, MD 21701, USA. 5ICGex Next-Generation Sequencing Platform, PSL Université, Research Center, Institut Curie, 75005 Paris, France. 6Inserm U830, PSL Université, Research Center, Institut Curie, 75005 Paris, France; SIREDO Oncology Centre, Institut Curie, 75005 Paris, France; Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland. 7SIREDO Oncology Centre, Institut Curie, 75005 Paris, France; Unité de Génétique Somatique, Department of Genetics, Institut Curie Hospital, 75005 Paris, France. 8Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU, 80337 Munich, Germany. 9SIREDO Oncology Centre, Institut Curie, 75005 Paris, France. 10Department of Oncology for Child and Adolescent, Institut Gustave Roussy, 94800 Villejuif, France. 11Institute for Paediatric Haematology and Oncology, Leon Bérard Cancer Centre, University of Lyon, 69008 Lyon, France. 12Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA; Genome Modification Core Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA. 13Cancer Prevention and Clinical Statistics Programs, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. 14University Children's Hospital of Heidelberg, 69120 Heidelberg, Germany. 15Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany. 16Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 80333 Munich, Germany. 17Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, 80539 Munich, Germany. 18Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Institute of Pathology, Faculty of Medicine, LMU, 80337 Munich, Germany. 19University Children's Hospital of Essen, 45147 Essen, Germany. 20Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 21Institute for Cancer Outcomes and Survivorship, University of Alabama, Birmingham, AL 35294, USA. 22Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU, 80337 Munich, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany. 23Gerhard- Domagk Institute of Pathology, University Hospital of Münster, 48149 Münster, Germany. 24University Children's Hospital of Erlangen, 91054 Erlangen, Germany. 25Department of Population Science, American Cancer Society, Atlanta, GA, USA. 26Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU, 80337 Munich, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 27Inserm U830, PSL Université, Research Center, Institut Curie, 75005 Paris, France; SIREDO Oncology Centre, Institut Curie, 75005 Paris, France. Electronic address: olivier.delattre@curie.fr. 28Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: mitchell.machiela@nih.gov.
    1. Year: 2023
    2. Date: Mar 2
    3. Epub Date: 2023 02 08
  2. Journal: American Journal of Human Genetics
    1. 110
    2. 3
    3. Pages: 427-441
  4. Type of Article: Article
  1. Abstract:

    Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation. Published by Elsevier Inc.

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  2. DOI: 10.1016/j.ajhg.2023.01.017
  3. PMID: 36787739
  4. View record in Web of Science®
  5. WOS: 000982413800001
  6. PII : S0002-9297(23)00017-4

Library Notes

  1. Fiscal Year: FY2022-2023
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