title: Breast tumor copy number aberration phenotypes and genomic instability.
abstract: BACKGROUND
  Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes.
  
  
  METHODS
  We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability.
  
  
  RESULTS
  We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability.
  
  
  CONCLUSIONS
  Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, CA 94143, USA. fridlyand@cc.ucsf.edu
authors.forename: Jane
authors.initials: J
authors.lastname: Fridlyand
authors.forename: Antoine M
authors.initials: AM
authors.lastname: Snijders
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Adam
authors.initials: A
authors.lastname: Olshen
authors.forename: Richard
authors.initials: R
authors.lastname: Segraves
authors.forename: Shanaz
authors.initials: S
authors.lastname: Dairkee
authors.forename: Taku
authors.initials: T
authors.lastname: Tokuyasu
authors.forename: Britt Marie
authors.initials: BM
authors.lastname: Ljung
authors.forename: Ajay N
authors.initials: AN
authors.lastname: Jain
authors.forename: Jane
authors.initials: J
authors.lastname: McLennan
authors.forename: John
authors.initials: J
authors.lastname: Ziegler
authors.forename: Koei
authors.initials: K
authors.lastname: Chin
authors.forename: Sandy
authors.initials: S
authors.lastname: Devries
authors.forename: Heidi
authors.initials: H
authors.lastname: Feiler
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Frederic
authors.initials: F
authors.lastname: Waldman
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinkel
authors.forename: Donna G
authors.initials: DG
authors.lastname: Albertson
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics* / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000235:genetics*; D050684:E2F Transcription Factors / Q000235:genetics / Q000502:physiology*; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D042822:Genomic Instability; D006801:Humans; D007621:Karyotyping; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D016615:Telomere / Q000648:ultrastructure
chemical_list: D004273:DNA, Neoplasm; D050684:E2F Transcription Factors; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein