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Leukemia. 2017 Oct;31(10):2048-2056. doi: 10.1038/leu.2017.55. Epub 2017 Feb 15.

Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.

Author information

1
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Institute of Human Genetics, University Heidelberg, Heidelberg, Germany.
3
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, Heidelberg, Germany.
4
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
5
EMBL Heidelberg, Genome Biology, Heidelberg, Germany.
6
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
7
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany.
9
Department of Pediatric Oncology, University of Halle, Halle, Germany.
10
Division of Pediatric Hematology and Oncology, Goettingen, Germany.
11
Clinical Cooperation Group Osteosarcoma, Pediatric Oncology Center, Department of Pediatrics, Technical University Munich, Munich, Germany.
12
Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
13
Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
14
Department of Internal Medicine III, University of Ulm, Germany.
15
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
16
Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
17
Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv, Israel.
18
Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
19
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
20
Department of Paediatric Pulmonology, Allergy and Cystic Fibrosis, Children's Hospital, Goethe-University, Frankfurt, Germany.
21
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
22
Olgahospital Stuttgart, Children's Hospital, Klinikum Stuttgart, Stuttgart, Germany.
23
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
24
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

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.

PMID:
28196983
DOI:
10.1038/leu.2017.55
[Indexed for MEDLINE]

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