title: Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma.
abstract: BACKGROUND
  Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes--adenocarcinoma (AC) and squamous cell carcinoma (SqCC)--respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.
  
  
  RESULTS
  We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.
  
  
  CONCLUSIONS
  This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy. Please see later in the article for the Editors' Summary.
authors.affiliation: Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. wlockwood@bccrc.ca
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Raj
authors.initials: R
authors.lastname: Chari
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Cathie
authors.initials: C
authors.lastname: Garnis
authors.forename: Chad A
authors.initials: CA
authors.lastname: Malloff
authors.forename: Jennifer
authors.initials: J
authors.lastname: Campbell
authors.forename: Ariane C
authors.initials: AC
authors.lastname: Williams
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hwang
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Zhu
authors.forename: Timon P H
authors.initials: TP
authors.lastname: Buys
authors.forename: John
authors.initials: J
authors.lastname: Yee
authors.forename: John C
authors.initials: JC
authors.lastname: English
authors.forename: Calum
authors.initials: C
authors.lastname: Macaulay
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000502:physiology; D009928:Organ Specificity / Q000235:genetics; D018511:Systems Integration; D035361:Transcription Factor TFIIIB / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C416185:BRF2 protein, human; D014408:Biomarkers, Tumor; D035361:Transcription Factor TFIIIB