title: Principles of Reconstructing the Subclonal Architecture of Cancers.
abstract: Most cancers evolve from a single founder cell through a series of clonal expansions that are driven by somatic mutations. These clonal expansions can lead to several coexisting subclones sharing subsets of mutations. Analysis of massively parallel sequencing data can infer a tumor's subclonal composition through the identification of populations of cells with shared mutations. We describe the principles that underlie subclonal reconstruction through single nucleotide variants (SNVs) or copy number alterations (CNAs) from bulk or single-cell sequencing. These principles include estimating the fraction of tumor cells for SNVs and CNAs, performing clustering of SNVs from single- and multisample cases, and single-cell sequencing. The application of subclonal reconstruction methods is providing key insights into tumor evolution, identifying subclonal driver mutations, patterns of parallel evolution and differences in mutational signatures between cellular populations, and characterizing the mechanisms of therapy resistance, spread, and metastasis.
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.|The Francis Crick Institute, London NW1 1AT, United Kingdom.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Dentro
authors.affiliation: Big Data Institute, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: The Francis Crick Institute, London NW1 1AT, United Kingdom.|Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
mesh_terms: D000465:Algorithms; D060965:Clonal Evolution / Q000235:genetics*; D056915:DNA Copy Number Variations; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide