title: Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.
abstract: Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ratnaparkhe
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hlevnjak
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kolb
authors.affiliation: Institute of Human Genetics, University Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K K
authors.initials: KK
authors.lastname: Maass
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Devens
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rode
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Pastorczak
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Mlynarski
authors.affiliation: EMBL Heidelberg, Genome Biology, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sungalee
authors.affiliation: EMBL Heidelberg, Genome Biology, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Korbel
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hoell
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Milde
authors.affiliation: Department of Pediatric Oncology, University of Halle, Halle, Germany.|Division of Pediatric Hematology and Oncology, Goettingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kramm
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Pediatric Oncology Center, Department of Pediatrics, Technical University Munich, Munich, Germany.|Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Nathrath
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Chrzanowska
authors.affiliation: Department of Internal Medicine III, University of Ulm, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Tausch
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: M
authors.identifier: 0000-0002-7580-9184
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Taga
authors.affiliation: Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Constantini
authors.affiliation: Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Loeffen
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Meijerink
authors.affiliation: Department of Paediatric Pulmonology, Allergy and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zielen
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Gohring
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Olgahospital Stuttgart, Children's Hospital, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Maass
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kunz
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.
authors.forename: A E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.|Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Worst
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.|Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: D T
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.|Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.identifier: 0000-0001-8287-5967
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ernst
mesh_terms: D000293:Adolescent; D001260:Ataxia Telangiectasia / Q000150:complications / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D002877:Chromosomes, Human / Q000648:ultrastructure; D000072837:Chromothripsis; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D059506:Telomere Shortening / Q000235:genetics; D059467:Transcriptome
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins