Signatures of copy number alterations in human cancer

Christopher D. Steele, Ammal Abbasi, S. M. Ashiqul Islam, Amy L. Bowes, Azhar Khandekar, Kerstin Haase, Shadi Hames-Fathi, Dolapo Ajayi, Annelien Verfaillie, Pawan Dhami, Alex McLatchie, Matt Lechner, Nicholas Light, Adam Shlien, David Malkin, Andrew Feber, Paula Proszek, Tom Lesluyes, Fredrik Mertens, Adrienne M. Flanagan, Maxime Tarabichi, Peter Loo, Ludmil B. Alexandrov () and Nischalan Pillay ()
Additional contact information
Christopher D. Steele: Cancer Institute, University College London
Ammal Abbasi: UC San Diego
S. M. Ashiqul Islam: UC San Diego
Amy L. Bowes: Cancer Institute, University College London
Azhar Khandekar: UC San Diego
Kerstin Haase: The Francis Crick Institute
Shadi Hames-Fathi: Cancer Institute, University College London
Dolapo Ajayi: Cancer Institute, University College London
Annelien Verfaillie: The Francis Crick Institute
Pawan Dhami: CRUK–UCL Cancer Institute Translational Technology Platform (Genomics)
Alex McLatchie: CRUK–UCL Cancer Institute Translational Technology Platform (Genomics)
Matt Lechner: UCL Cancer Institute
Nicholas Light: The Hospital for Sick Children
Adam Shlien: University of Toronto
David Malkin: The Hospital for Sick Children
Andrew Feber: Institute of Cancer Research
Paula Proszek: Institute of Cancer Research
Tom Lesluyes: The Francis Crick Institute
Fredrik Mertens: Lund University
Adrienne M. Flanagan: Cancer Institute, University College London
Maxime Tarabichi: The Francis Crick Institute
Peter Loo: The Francis Crick Institute
Ludmil B. Alexandrov: UC San Diego
Nischalan Pillay: Cancer Institute, University College London

Nature, 2022, vol. 606, issue 7916, 984-991

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41586-022-04738-6

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