title: Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes.
abstract: BACKGROUND
  It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements.
  
  
  RESULTS
  We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing-55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer-in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator.
  
  
  CONCLUSIONS
  This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important classes of mutation in breast cancer, with a typical breast cancer expressing many fusion genes.
authors.affiliation: Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Ina
authors.initials: I
authors.lastname: Schulte
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Batty
authors.forename: Jessica C M
authors.initials: JC
authors.lastname: Pole
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Blood
authors.forename: Steven
authors.initials: S
authors.lastname: Mo
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ng
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Howe
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Karen D
authors.initials: KD
authors.lastname: Howarth
authors.forename: Paul A W
authors.initials: PA
authors.lastname: Edwards
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D055028:Comparative Genomic Hybridization / Q000379:methods; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D015514:Oncogene Proteins, Fusion