Clonal heterogeneity in cancer
Through phylogenetic reconstruction and mathematical modeling we set bounds on the number of mutations and clones in the cancer ecosystem. While mutations of the earliest pathogenic genetic drivers are truncal, we demonstrate that most other likely passenger mutations, copy-number alterations, and clones arise after the cancer has spread and, because of polyclonal and polyphyletic seeding, are confined to individual metastatic sites. We find that single-tissue sequencing tends to overestimate mutation clonality and apart from truncal drivers underestimate mutation rates, for both individual patients and cohorts. This study highlights the independent evolution of metastatic lesions, and its implications for diagnostic and targeted therapy strategies.