title: The relative timing of mutations in a breast cancer genome.
abstract: Many tumors have highly rearranged genomes, but a major unknown is the relative importance and timing of genome rearrangements compared to sequence-level mutation. Chromosome instability might arise early, be a late event contributing little to cancer development, or happen as a single catastrophic event. Another unknown is which of the point mutations and rearrangements are selected. To address these questions we show, using the breast cancer cell line HCC1187 as a model, that we can reconstruct the likely history of a breast cancer genome. We assembled probably the most complete map to date of a cancer genome, by combining molecular cytogenetic analysis with sequence data. In particular, we assigned most sequence-level mutations to individual chromosomes by sequencing of flow sorted chromosomes. The parent of origin of each chromosome was assigned from SNP arrays. We were then able to classify most of the mutations as earlier or later according to whether they occurred before or after a landmark event in the evolution of the genome, endoreduplication (duplication of its entire genome). Genome rearrangements and sequence-level mutations were fairly evenly divided earlier and later, suggesting that genetic instability was relatively constant throughout the life of this tumor, and chromosome instability was not a late event. Mutations that caused chromosome instability would be in the earlier set. Strikingly, the great majority of inactivating mutations and in-frame gene fusions happened earlier. The non-random timing of some of the mutations may be evidence that they were selected.
authors.affiliation: Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Scott
authors.initials: S
authors.lastname: Newman
authors.forename: Karen D
authors.initials: KD
authors.lastname: Howarth
authors.forename: Chris D
authors.initials: CD
authors.lastname: Greenman
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.forename: Paul A W
authors.initials: PA
authors.lastname: Edwards
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013997:Time Factors; D014407:Tumor Cells, Cultured