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Nature. 2020 Feb;578(7793):112-121. doi: 10.1038/s41586-019-1913-9. Epub 2020 Feb 5.

Patterns of somatic structural variation in human cancer genomes.

Author information

1
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
2
Totient Inc, Cambridge, MA, USA.
3
The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
4
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, USA.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Weill Cornell Medical College, New York, NY, USA.
7
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
8
Department of Molecular Biology, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA.
9
New York Genome Center, New York, NY, USA.
10
Biotech Research & Innovation Centre (BRIC), The Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. joachim.weischenfeldt@bric.ku.dk.
11
The Broad Institute of Harvard and MIT, Cambridge, MA, USA. rameen_beroukhim@dfci.harvard.edu.
12
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, USA. rameen_beroukhim@dfci.harvard.edu.
13
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
14
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. pc8@sanger.ac.uk.
15
Department of Haematology, University of Cambridge, Cambridge, UK. pc8@sanger.ac.uk.

Abstract

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1-7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

PMID:
32025012
PMCID:
PMC7025897
[Available on 2020-08-05]
DOI:
10.1038/s41586-019-1913-9

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