Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.In recent years, several large-scale whole-genome sequencing (WGS) analysis efforts have yielded valuable insights into the diversity of the molecular processes that drive different types of adult 1,2 and paediatric 3,4 cancer and have fuelled the promises of genome-driven oncology care 5 . However, most analyses were done on primary tumour material, whereas metastatic cancers-which cause the bulk of the disease burden and 90% of all cancer deaths-have been less comprehensively studied at the whole-genome level, with previous efforts focusing on tumourspecific cohorts 6-8 or at a targeted gene panel 9 or exome level 10 . As cancer genomes evolve over time, both in the highly heterogeneous primary tumour mass and as disseminated metastatic cells 11,12 , a better understanding of metastatic cancer genomes will be highly valuable to improve on adapting treatments for late-stage cancers.Here we describe the pan-cancer whole-genome landscape of metastatic cancers based on 2,520 paired tumour (106× average depth) and normal (blood, 38×) genomes from 2,399 patients ( Supplementary Tables 1 and 2, Extended Data Fig. 1). The sample distribution over age and primary tumour types broadly reflects the incidence of solid cancers in the Western world, including rare cancers (Fig. 1a). Sequencing data were analysed using an optimized bioinformatic pipeline based on open source tools (Methods, Supplementary Information) and identified a total of 59,472,629 single nucleotide varian...
