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Patterns of somatic structural variation in human cancer genomes

Li, Yilong ; Roberts, Nicola D ; Wala, Jeremiah A ; Shapira, Ofer ; Schumacher, Steven E ; Kumar, Kiran ; Khurana, Ekta ; Waszak, Sebastian ; Korbel, Jan O and Haber, James E , et al. (2020) In Nature 578(7793). p.112-121
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... (More)

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.

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publication status
published
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keywords
Gene Rearrangement/genetics, Genetic Variation, Genome, Human/genetics, Genomics, Humans, Mutagenesis, Insertional, Neoplasms/genetics, Telomerase/genetics
in
Nature
volume
578
issue
7793
pages
112 - 121
publisher
Nature Publishing Group
external identifiers
  • scopus:85078674086
  • pmid:32025012
ISSN
0028-0836
DOI
10.1038/s41586-019-1913-9
language
English
LU publication?
yes
id
5ad43c7f-63e9-4e76-bae5-7ba7012fa3df
date added to LUP
2023-03-29 17:15:08
date last changed
2024-04-18 20:29:05
@article{5ad43c7f-63e9-4e76-bae5-7ba7012fa3df,
  abstract     = {{<p>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.</p>}},
  author       = {{Li, Yilong and Roberts, Nicola D and Wala, Jeremiah A and Shapira, Ofer and Schumacher, Steven E and Kumar, Kiran and Khurana, Ekta and Waszak, Sebastian and Korbel, Jan O and Haber, James E and Imielinski, Marcin and Weischenfeldt, Joachim and Beroukhim, Rameen and Campbell, Peter J}},
  issn         = {{0028-0836}},
  keywords     = {{Gene Rearrangement/genetics; Genetic Variation; Genome, Human/genetics; Genomics; Humans; Mutagenesis, Insertional; Neoplasms/genetics; Telomerase/genetics}},
  language     = {{eng}},
  number       = {{7793}},
  pages        = {{112--121}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Patterns of somatic structural variation in human cancer genomes}},
  url          = {{http://dx.doi.org/10.1038/s41586-019-1913-9}},
  doi          = {{10.1038/s41586-019-1913-9}},
  volume       = {{578}},
  year         = {{2020}},
}