Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma.
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.
Lockwood
William W
WW
Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. wlockwood@bccrc.ca
Chari
Raj
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Coe
Bradley P
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Kelsie L
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Garnis
Cathie
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Malloff
Chad A
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Campbell
Jennifer
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Williams
Ariane C
AC
Hwang
Dorothy
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Zhu
Chang-Qi
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Buys
Timon P H
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Yee
John
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English
John C
JC
Macaulay
Calum
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Tsao
Ming-Sound
MS
Gazdar
Adi F
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Minna
John D
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Lam
Stephen
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Lam
Wan L
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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
C416185:BRF2 protein, human; D014408:Biomarkers, Tumor; D035361:Transcription Factor TFIIIB