title: High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization.
abstract: BACKGROUND
  Genomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution.
  
  
  METHODS
  We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines.
  
  
  RESULTS
  Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses.
  
  
  CONCLUSIONS
  High resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. tnaylor@mail.med.upenn.edu
authors.forename: Tara L
authors.initials: TL
authors.lastname: Naylor
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Theresa
authors.initials: T
authors.lastname: Colligon
authors.forename: Q C
authors.initials: QC
authors.lastname: Yu
authors.forename: Virginia
authors.initials: V
authors.lastname: Clemmer
authors.forename: Tal Z
authors.initials: TZ
authors.lastname: Zaks
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012680:Sensitivity and Specificity
chemical_list: D004273:DNA, Neoplasm; D051417:Focal Adhesion Kinase 1; D018719:Erb-b2 Receptor Tyrosine Kinases; C496050:PTK2 protein, human