title: Identification of neutral tumor evolution across cancer types.
abstract: Despite extraordinary efforts to profile cancer genomes, interpreting the vast amount of genomic data in the light of cancer evolution remains challenging. Here we demonstrate that neutral tumor evolution results in a power-law distribution of the mutant allele frequencies reported by next-generation sequencing of tumor bulk samples. We find that the neutral power law fits with high precision 323 of 904 cancers from 14 types and from different cohorts. In malignancies identified as evolving neutrally, all clonal selection seemingly occurred before the onset of cancer growth and not in later-arising subclones, resulting in numerous passenger mutations that are responsible for intratumoral heterogeneity. Reanalyzing cancer sequencing data within the neutral framework allowed the measurement, in each patient, of both the in vivo mutation rate and the order and timing of mutations. This result provides a new way to interpret existing cancer genomic data and to discriminate between functional and non-functional intratumoral heterogeneity.
authors.affiliation: Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.|Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.|Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, WC1E 6BT, UK.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Werner
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.|Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Barnes
authors.affiliation: Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sottoriva
mesh_terms: D002999:Clone Cells; D005787:Gene Frequency; D040961:Genetic Drift; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000235:genetics*