Signatures of copy number alterations in human cancer

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 aneuploidy 1 , 2 . These copy number alte...

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Veröffentlicht in:Nature (London) Jg. 606; H. 7916; S. 984 - 991
Hauptverfasser: Steele, Christopher D., Abbasi, Ammal, Islam, S. M. Ashiqul, Bowes, Amy L., Khandekar, Azhar, Haase, Kerstin, Hames-Fathi, Shadi, Ajayi, Dolapo, Verfaillie, Annelien, Dhami, Pawan, McLatchie, Alex, Lechner, Matt, Light, Nicholas, Shlien, Adam, Malkin, David, Feber, Andrew, Proszek, Paula, Lesluyes, Tom, Mertens, Fredrik, Flanagan, Adrienne M., Tarabichi, Maxime, Van Loo, Peter, Alexandrov, Ludmil B., Pillay, Nischalan
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 30.06.2022
Nature Publishing Group
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Aneuploidy
Basic Medicine
Bisulfite
Cancer
Cancer and Oncology
Cancer och onkologi
Chromosomes
Chromothripsis
Clinical Medicine
Copy number
Deoxyribonucleic acid
DNA
DNA Copy Number Variations - genetics
DNA microarrays
DNA Mutational Analysis
DNA sequencing
Exome Sequencing
Genomes
Genomic instability
Haploidy
Health risks
Heterozygosity
Homologous recombination
Homologous Recombination - genetics
Homology
Humanities and Social Sciences
Humans
Klinisk medicin
Loss of heterozygosity
Loss of Heterozygosity - genetics
MDM2 protein
Medical and Health Sciences
Medical Genetics and Genomics (including Gene Therapy)
Medicin och hälsovetenskap
Medicinsk genetik och genomik (Här ingår: Genterapi)
Medicinska och farmaceutiska grundvetenskaper
multidisciplinary
Mutation
Neoplasms - genetics
Neoplasms - pathology
Ovaries
Risk analysis
Risk factors
Science
Science (multidisciplinary)
Signatures
Whole genome sequencing
ISSN:0028-0836, 1476-4687, 1476-4687
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Zusammenfassung: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 aneuploidy 1 , 2 . These copy number alterations contribute to cancer initiation, progression and therapeutic resistance 3 – 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 Atlas 6 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. A new framework enables a pan-cancer reference set of copy number signatures derived from allele-specific profiles from different experimental assays.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-022-04738-6