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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Vydáno v:	Nature (London) Ročník 606; číslo 7916; s. 984 - 991
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 30.06.2022 Nature Publishing Group
Témata:	13 13/31 45/22 45/23 45/61 631/114/2785 631/67/69 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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-022-04738-6