Abstract

The cancer genome contains within it an archaeological record of its past. We developed approaches to disentangle the evolutionary history of cancers through whole genome sequencing, collectively termed “molecular archaeology of cancer”. In a pan-cancer analysis of 2,658 whole-genome sequenced tumours, we are gaining insights into the extent of intra-tumour heterogeneity in different cancer types and the order and timing of acquisition of genetic aberrations. We find that characteristic copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma, are found amongst the earliest events in tumour evolution. The early phases of oncogenesis are driven by point mutations in a restricted set of cancer genes, often including biallelic inactivation of tumour suppressors. By contrast, increased genomic instability, a more than three-fold diversification of driver genes, and an acceleration of mutational processes are features of later stages. Using clock-like mutations, we obtain estimates for whole genome duplications and subclonal diversification in chronological time. Our results suggest that driver mutations often precede diagnosis by many years, and in some cases decades.Taken together, these data indicate that most cancers commonly have several predefined and ordered event trajectories, pivotal for understanding tumour biology and guiding early cancer detection.