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.

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA 1 . The broad genomic complexity caused by CIN is a hallmark of cancer 2 ; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.CIN has complex consequences, including loss or amplification of driver genes, focal rearrangements, extrachromosomal DNA, micronuclei formation and activation of innate immune signalling 1 . This leads to associations with disease stage, metastasis, poor prognosis and therapeutic resistance 3 . The causes of CIN are also diverse and include mitotic errors, replication stress, homologous recombination deficiency (HRD), telomere crisis and breakage fusion bridge cycles, among others 1,4 .Because of the diversity of these causes and consequences, CIN is generally used as an umbrella term. Measures of CIN either divide tumours into broad categories of high or low CIN 5 , are restricted to a single aetiology such as HRD 6 , are limited to a particular genomic feature such as whole-chromosome-arm changes 7 , or can only be quantified in specific cancer types 8,9 . As a result, there is no systematic framework to comprehensively characterize the diversity, extent and origins of CIN pan-cancer, or to define how different types of CIN within a tumour relate to clinical phenotypes. Here we present a robust analysis framework to quantitatively measure different types of CIN across cancer types.

All scripts, motifs and data presented in this article are available online at http://research.imb.uq.edu.au/t.bailey/supplementary_data/McLeay2011a.