Integrative Genomic Analyses Identify BRF2 as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma
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{"title"=>"Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma", "type"=>"journal", "authors"=>[{"first_name"=>"William W.", "last_name"=>"Lockwood", "scopus_author_id"=>"11939640000"}, {"first_name"=>"Raj", "last_name"=>"Chari", "scopus_author_id"=>"11939421400"}, {"first_name"=>"Bradley P.", "last_name"=>"Coe", "scopus_author_id"=>"7006220576"}, {"first_name"=>"Kelsie L.", "last_name"=>"Thu", "scopus_author_id"=>"26432362800"}, {"first_name"=>"Cathie", "last_name"=>"Garnis", "scopus_author_id"=>"6601917768"}, {"first_name"=>"Chad A.", "last_name"=>"Malloff", "scopus_author_id"=>"6507762829"}, {"first_name"=>"Jennifer", "last_name"=>"Campbell", "scopus_author_id"=>"57198449547"}, {"first_name"=>"Ariane C.", "last_name"=>"Williams", "scopus_author_id"=>"15726964500"}, {"first_name"=>"Dorothy", "last_name"=>"Hwang", "scopus_author_id"=>"36438491700"}, {"first_name"=>"Chang Qi", "last_name"=>"Zhu", "scopus_author_id"=>"8537385600"}, {"first_name"=>"Timon P.H.", "last_name"=>"Buys", "scopus_author_id"=>"8787666200"}, {"first_name"=>"John", "last_name"=>"Yee", "scopus_author_id"=>"7203044535"}, {"first_name"=>"John C.", "last_name"=>"English", "scopus_author_id"=>"7202807133"}, {"first_name"=>"Calum", "last_name"=>"MacAulay", "scopus_author_id"=>"35370099900"}, {"first_name"=>"Ming Sound", "last_name"=>"Tsao", "scopus_author_id"=>"7102152241"}, {"first_name"=>"Adi F.", "last_name"=>"Gazdar", "scopus_author_id"=>"35372587300"}, {"first_name"=>"John D.", "last_name"=>"Minna", "scopus_author_id"=>"35380041500"}, {"first_name"=>"Stephen", "last_name"=>"Lam", "scopus_author_id"=>"55193690600"}, {"first_name"=>"Wan L.", "last_name"=>"Lam", "scopus_author_id"=>"7203021871"}], "year"=>2010, "source"=>"PLoS Medicine", "identifiers"=>{"sgr"=>"77955034636", "doi"=>"10.1371/journal.pmed.1000315", "pui"=>"359258175", "pmid"=>"20668658", "scopus"=>"2-s2.0-77955034636", "issn"=>"15491277", "isbn"=>"1549-1676 (Electronic) 1549-1277 (Linking)"}, "id"=>"785e61cb-a892-3cd5-b363-6649e91c5881", "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.\\n\\nMETHODS AND FINDINGS: 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.\\n\\nCONCLUSIONS: 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.", "link"=>"http://www.mendeley.com/research/integrative-genomic-analyses-identify-brf2-novel-lineagespecific-oncogene-lung-squamous-cell-carcino-1", "reader_count"=>16, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>3, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>3, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Mathematics"=>1, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Mathematics"=>{"Mathematics"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Turkey"=>1}, "group_count"=>2}

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  • {"files"=>["https://ndownloader.figshare.com/files/417903", "https://ndownloader.figshare.com/files/417934", "https://ndownloader.figshare.com/files/417970", "https://ndownloader.figshare.com/files/417998", "https://ndownloader.figshare.com/files/418041", "https://ndownloader.figshare.com/files/418073", "https://ndownloader.figshare.com/files/418141", "https://ndownloader.figshare.com/files/418184", "https://ndownloader.figshare.com/files/418228", "https://ndownloader.figshare.com/files/418268", "https://ndownloader.figshare.com/files/418294", "https://ndownloader.figshare.com/files/418340", "https://ndownloader.figshare.com/files/418377", "https://ndownloader.figshare.com/files/418434"], "description"=>"<div><h3>Background</h3><p>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.</p> <h3>Methods and Findings</h3><p>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 <em>BRF2</em>, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of <em>BRF2</em>, 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 <em>BRF2</em> 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 <em>BRF2</em>, but not AC cells. Frequent activation of <em>BRF2</em> in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that <em>BRF2</em> expression is an early event in cancer development of this cell lineage.</p> <h3>Conclusions</h3><p>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 <em>BRF2</em> 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.</p> <h3></h3><p><em>Please see later in the article for the Editors' Summary</em></p> </div>", "links"=>[], "tags"=>["integrative", "genomic", "analyses", "lineage-specific", "oncogene", "squamous", "carcinoma"], "article_id"=>142514, "categories"=>["Genetics", "Cell Biology", "Cancer"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1000315.s001", "https://dx.doi.org/10.1371/journal.pmed.1000315.s002", "https://dx.doi.org/10.1371/journal.pmed.1000315.s003", "https://dx.doi.org/10.1371/journal.pmed.1000315.s004", "https://dx.doi.org/10.1371/journal.pmed.1000315.s005", "https://dx.doi.org/10.1371/journal.pmed.1000315.s006", "https://dx.doi.org/10.1371/journal.pmed.1000315.s007", "https://dx.doi.org/10.1371/journal.pmed.1000315.s008", "https://dx.doi.org/10.1371/journal.pmed.1000315.s009", "https://dx.doi.org/10.1371/journal.pmed.1000315.s010", "https://dx.doi.org/10.1371/journal.pmed.1000315.s011", "https://dx.doi.org/10.1371/journal.pmed.1000315.s012", "https://dx.doi.org/10.1371/journal.pmed.1000315.s013", "https://dx.doi.org/10.1371/journal.pmed.1000315.s014"], "stats"=>{"downloads"=>106, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Integrative_Genomic_Analyses_Identify_BRF2_as_a_Novel_Lineage_Specific_Oncogene_in_Lung_Squamous_Cell_Carcinoma/142514", "title"=>"Integrative Genomic Analyses Identify <em>BRF2</em> as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-07-27 00:41:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/838621"], "description"=>"<p>(A) Frequent copy number increase of Chromosome arm 8p in 20 bronchial CIS lesions. Samples are ordered in columns and ordered by genomic position along 8p. The color scale ranges from white (neutral copy number, N) to black (amplification, Amp). Data from representative normal lung (N) and SqCC tumor samples (T) are displayed to the left and right of the CIS cases respectively. (B) Amplification score along Chromosome 8p for the 20 CIS cases. Regions of amplification were defined for each case and summarized across the group to determine the incidence of occurrence. Dashed lines represent the positions of <i>BRF2</i>, <i>WHSC1LC</i>, and <i>FGFR1</i> from top to bottom respectively. (C) Array CGH copy number profiles for two individual CIS cases with 8p amplification. Each black dot represents an array element ordered by genomic position. Those shifted to the left of the middle line (N) have decreased copy number (Del), whereas those shifted to the right have increased copy number (Amp). Dashed lines represent the positions of the three genes as in (B). The region highlighted in orange represents the region of high-level amplification in each sample. The amplicon in CIS1 includes only <i>BRF2</i> with <i>WHSC1L1</i> and <i>FGFR1</i> outside or spanning the boundaries while the amplicon in CIS2 contains all three genes. (D) Immunostaining of CIS2 with anti-<i>BRF2</i> polyclonal antibody revealed elevated staining in CIS epithelia compared with normal from the same tissue section.</p>", "links"=>[], "tags"=>["overexpression", "brf2", "preinvasive", "sqcc"], "article_id"=>509043, "categories"=>["Genetics", "Cell Biology", "Cancer"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000315.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Amplification_and_overexpression_of_BRF2_in_preinvasive_SqCC_lesions_/509043", "title"=>"Amplification and overexpression of BRF2 in preinvasive SqCC lesions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-27 02:30:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/838724"], "description"=>"<p>Immunostaining of 21 lung SqCC precursor lesions with anti-<i>BRF2</i> polyclonal antibody revealed a monotonic increase in BRF2 expression with increasing histopathology grade. The area within the diagnostic area was scored as follows: 0, no positive staining; 1<25% positive cells; 2≤50% positive cells; 3≤75% positive cells; and 4<100% positive cells. Each sample is represented by a single dot above its corresponding grade with the horizontal black lines representing the median IHC score for each grade. Red samples highlight multiple grades taken from the same individual patient.</p>", "links"=>[], "tags"=>["sqcc", "precancerous"], "article_id"=>509156, "categories"=>["Genetics", "Cell Biology", "Cancer"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000315.g005", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BRF2_expression_in_SqCC_precancerous_stages_/509156", "title"=>"BRF2 expression in SqCC precancerous stages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-27 02:32:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/838344"], "description"=>"<p>(A) Frequency of gain/amplification along Chromosome arm 8p is depicted for 103 AC (red) and 58 SqCC clinical tumor specimens (blue). (B) The significance of copy number disparity (inverse <i>p</i>-value) between AC and SqCC cell type groups is depicted for 8p. Solid black lines represent regions considered statistically different (<i>p</i>≤0.01), whereas dashed lines are not. (C) Relative expression for genes within regions of copy number difference, which were also expressed at significantly higher levels in SqCC (<i>n</i> = 13) compared to AC (<i>n</i> = 34) tumors (<i>p</i>≤0.01). The color scale ranges from black (low expression) to white (high expression).</p>", "links"=>[], "tags"=>["8p", "amplification", "nsclc", "restricted", "sqcc"], "article_id"=>508741, "categories"=>["Genetics", "Cell Biology", "Cancer"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000315.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chromosome_8p_amplification_in_NSCLC_is_restricted_to_the_SqCC_lineage_/508741", "title"=>"Chromosome 8p amplification in NSCLC is restricted to the SqCC lineage.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-27 02:25:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/838499"], "description"=>"<p>(A) Concordance between <i>BRF2</i> copy number (array CGH), expression (qRT-PCR), protein (immunoblot) levels, and Pol III transcript levels (northern blot) in H520, H1395, and H2347 NSCLC cell lines. (B) Decrease in <i>BRF2</i> mRNA levels in H520 cells expressing shRNAs targeting <i>BRF2</i> relative to those expressing a negative vector control (mean ± SEM of triplicate samples). (C) <i>BRF2</i> knockdown results in decreased cell proliferation in H520 cells with amplification and overexpression as measured by MTT assay relative to vector control (mean ± SEM of triplicate samples). (D) <i>BRF2</i> knockdown reduces colony growth of H520 cells in soft-agar relative to vector control (mean ± SEM of triplicate samples). (E) siRNA transfection results in decreased cell proliferation as measured by the MTT assay in H520 SqCC cells but not H1395 AC cells relative to nontargeting siRNA control (mean ± SEM of triplicate experiments). Increased saturation density in both (F) BRF2 expressing HBEC and (G) BRF2 and p53RNAi expressing HBEC compared to their respective controls (mean ± SEM of triplicate samples). *, <i>p</i><0.05; **, <i>p</i><0.01; ***, <i>p</i><0.001 (Student's <i>t</i> test; compared to control).</p>", "links"=>[], "tags"=>["activation", "contributes"], "article_id"=>508936, "categories"=>["Genetics", "Cell Biology", "Cancer"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000315.g003", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BRF2_activation_contributes_to_cell_growth_and_proliferation_/508936", "title"=>"BRF2 activation contributes to cell growth and proliferation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-27 02:28:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/838418"], "description"=>"<p>(A) Comparison of <i>BRF2</i> mRNA expression values for AC (<i>n</i> = 34) and SqCC (<i>n</i> = 13) tumors (<i>p</i> = 0.0056). Box-plots depict the median group expression (red line), the 25th and 75th percentiles (blue box), and the limits of 95% of samples for each group (outside lines) with values for all other samples represented by red crosses. Expression values for all plots are in arbitrary log10 units. (B) Spearman's correlation of Z-transformed array CGH copy number ratios and expression values for <i>BRF2</i> in 13 SqCC tumors (correlation coefficient = 0.87). Each diamond represents an individual sample. (C) Comparison of <i>BRF2</i> expression between SqCC tumors with neutral copy number status (<i>n</i> = 4) and SqCC tumors with gain/amplification (<i>n</i> = 6) (<i>p</i> = 0.048). (D) Difference in <i>BRF2</i> expression levels between 67 exfoliated bronchial cell samples from cancer-free patients and 53 SqCC tumors from an independent sample set (<i>p</i><1.0×10<sup>−8</sup>).</p>", "links"=>[], "tags"=>["lineage-specific", "oncogene", "targeted", "amplification"], "article_id"=>508851, "categories"=>["Genetics", "Cell Biology", "Cancer"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1000315.g002", "stats"=>{"downloads"=>4, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BRF2_is_a_lineage_specific_oncogene_targeted_by_amplification_in_SqCC_/508851", "title"=>"<i>BRF2</i> is a lineage-specific oncogene targeted by amplification in SqCC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-27 02:27:31"}

PMC Usage Stats | Further Information

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Relative Metric

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