Format

Send to

Choose Destination
Nat Genet. 2020 Mar;52(3):306-319. doi: 10.1038/s41588-019-0562-0. Epub 2020 Feb 5.

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Author information

1
Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
2
Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
3
Biomedical Research Centre (CINBIO), University of Vigo, Vigo, Spain.
4
Transmissible Cancer Group, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
5
Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
6
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
7
The Francis Crick Institute, London, UK.
8
Department of Human Genetics, University of Leuven, Leuven, Belgium.
9
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
10
Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Cambridge, UK.
11
Department of Biochemistry, Genetics and Immunology, University of Vigo, Vigo, Spain.
12
Galicia Sur Health Research Institute, Vigo, Spain.
13
Barcelona Supercomputing Center (BSC-CNS), Barcelona, Spain.
14
Faculty of Science and Technology, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
15
Experimental Cancer Genetics, Wellcome Sanger Institute, Cambridge, UK.
16
Oxford Big Data Institute, University of Oxford, Oxford, UK.
17
DNA Repair and Genome Integrity, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
18
Department of Biochemistry and Molecular Biology, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
19
Medical Research Council (MRC) Cancer Unit, University of Cambridge, Cambridge, UK.
20
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Baltimore, MD, USA.
21
Department of Pathology, University of Cambridge, Cambridge, UK.
22
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
23
Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
24
Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
25
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
26
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
27
Department of Genetics and Informatics Institute, University of Alabama at Birmingham (UAB) School of Medicine, Birmingham, AL, USA.
28
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
29
The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
30
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
31
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
32
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
33
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
34
Department of Computer Science, Yale University, New Haven, CT, USA.
35
Department of Human Genetics, McGill University, Montreal, Québec, Canada.
36
Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy.
37
Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
38
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
39
Oxford NIHR Biomedical Research Centre, Oxford, UK.
40
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Baltimore, MD, USA.
41
Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Cambridge, UK. pc8@sanger.ac.uk.
42
Department of Haematology, University of Cambridge, Cambridge, UK. pc8@sanger.ac.uk.
43
Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. jose.mc.tubio@usc.es.
44
Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela, Spain. jose.mc.tubio@usc.es.
45
Biomedical Research Centre (CINBIO), University of Vigo, Vigo, Spain. jose.mc.tubio@usc.es.
46
Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Cambridge, UK. jose.mc.tubio@usc.es.

Abstract

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center