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Signatures of copy number alterations in human cancer

Steele, Christopher D ; Abbasi, Ammal ; Islam, S M Ashiqul ; Bowes, Amy L ; Khandekar, Azhar ; Haase, Kerstin ; Hames-Fathi, Shadi ; Ajayi, Dolapo ; Verfaillie, Annelien and Dhami, Pawan , et al. (2022) In Nature 606(7916). p.984-991
Abstract

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing... (More)

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
606
issue
7916
pages
8 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:35705804
  • scopus:85131930712
ISSN
0028-0836
DOI
10.1038/s41586-022-04738-6
language
English
LU publication?
yes
id
8eb51002-b2ce-475a-a2bd-8457f53c4fd1
date added to LUP
2022-06-30 11:36:35
date last changed
2024-05-18 20:41:04
@article{8eb51002-b2ce-475a-a2bd-8457f53c4fd1,
  abstract     = {{<p>Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.</p>}},
  author       = {{Steele, Christopher D and Abbasi, Ammal and Islam, S M Ashiqul and Bowes, Amy L and Khandekar, Azhar and Haase, Kerstin and Hames-Fathi, Shadi and Ajayi, Dolapo and Verfaillie, Annelien and Dhami, Pawan and McLatchie, Alex and Lechner, Matt and Light, Nicholas and Shlien, Adam and Malkin, David and Feber, Andrew and Proszek, Paula and Lesluyes, Tom and Mertens, Fredrik and Flanagan, Adrienne M and Tarabichi, Maxime and Van Loo, Peter and Alexandrov, Ludmil B and Pillay, Nischalan}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{7916}},
  pages        = {{984--991}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Signatures of copy number alterations in human cancer}},
  url          = {{http://dx.doi.org/10.1038/s41586-022-04738-6}},
  doi          = {{10.1038/s41586-022-04738-6}},
  volume       = {{606}},
  year         = {{2022}},
}