Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma.
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 the...
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doaj-f508a24cf83c448db07f726ff98ada8f2020-11-25T01:58:14ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762010-07-0177e100031510.1371/journal.pmed.1000315Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma.William W LockwoodRaj ChariBradley P CoeKelsie L ThuCathie GarnisChad A MalloffJennifer CampbellAriane C WilliamsDorothy HwangChang-Qi ZhuTimon P H BuysJohn YeeJohn C EnglishCalum MacaulayMing-Sound TsaoAdi F GazdarJohn D MinnaStephen LamWan L LamTraditionally, 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.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.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.http://europepmc.org/articles/PMC2910599?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
William W Lockwood Raj Chari Bradley P Coe Kelsie L Thu Cathie Garnis Chad A Malloff Jennifer Campbell Ariane C Williams Dorothy Hwang Chang-Qi Zhu Timon P H Buys John Yee John C English Calum Macaulay Ming-Sound Tsao Adi F Gazdar John D Minna Stephen Lam Wan L Lam |
spellingShingle |
William W Lockwood Raj Chari Bradley P Coe Kelsie L Thu Cathie Garnis Chad A Malloff Jennifer Campbell Ariane C Williams Dorothy Hwang Chang-Qi Zhu Timon P H Buys John Yee John C English Calum Macaulay Ming-Sound Tsao Adi F Gazdar John D Minna Stephen Lam Wan L Lam Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. PLoS Medicine |
author_facet |
William W Lockwood Raj Chari Bradley P Coe Kelsie L Thu Cathie Garnis Chad A Malloff Jennifer Campbell Ariane C Williams Dorothy Hwang Chang-Qi Zhu Timon P H Buys John Yee John C English Calum Macaulay Ming-Sound Tsao Adi F Gazdar John D Minna Stephen Lam Wan L Lam |
author_sort |
William W Lockwood |
title |
Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. |
title_short |
Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. |
title_full |
Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. |
title_fullStr |
Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. |
title_full_unstemmed |
Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. |
title_sort |
integrative genomic analyses identify brf2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Medicine |
issn |
1549-1277 1549-1676 |
publishDate |
2010-07-01 |
description |
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.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.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. |
url |
http://europepmc.org/articles/PMC2910599?pdf=render |
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