title: Signatures of mutation and selection in the cancer genome.
abstract: The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.forename: Chris D
authors.initials: CD
authors.lastname: Greenman
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Andrews
authors.forename: Gemma
authors.initials: G
authors.lastname: Buck
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Beare
authors.forename: Calli
authors.initials: C
authors.lastname: Latimer
authors.forename: Sara
authors.initials: S
authors.lastname: Widaa
authors.forename: Jonathon
authors.initials: J
authors.lastname: Hinton
authors.forename: Ciara
authors.initials: C
authors.lastname: Fahey
authors.forename: Beiyuan
authors.initials: B
authors.lastname: Fu
authors.forename: Sajani
authors.initials: S
authors.lastname: Swamy
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Dalgliesh
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
mesh_terms: D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020161:Physical Chromosome Mapping; D015203:Reproducibility of Results; D012641:Selection, Genetic / Q000235:genetics*