TY - JOUR
T1 - Signatures of copy number alterations in human cancer
AU - Steele, Christopher D
AU - Abbasi, Ammal
AU - Islam, S M Ashiqul
AU - Bowes, Amy L
AU - Khandekar, Azhar
AU - Haase, Kerstin
AU - Hames-Fathi, Shadi
AU - Ajayi, Dolapo
AU - Verfaillie, Annelien
AU - Dhami, Pawan
AU - McLatchie, Alex
AU - Lechner, Matt
AU - Light, Nicholas
AU - Shlien, Adam
AU - Malkin, David
AU - Feber, Andrew
AU - Proszek, Paula
AU - Lesluyes, Tom
AU - Mertens, Fredrik
AU - Flanagan, Adrienne M
AU - Tarabichi, Maxime
AU - Van Loo, Peter
AU - Alexandrov, Ludmil B
AU - Pillay, Nischalan
PY - 2022/6/15
Y1 - 2022/6/15
N2 - 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.
AB - 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.
U2 - 10.1038/s41586-022-04738-6
DO - 10.1038/s41586-022-04738-6
M3 - Article
C2 - 35705804
SN - 0028-0836
VL - 606
SP - 984
EP - 991
JO - Nature
JF - Nature
IS - 7916
ER -