Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival
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{"title"=>"Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival", "type"=>"journal", "authors"=>[{"first_name"=>"Maria Teresa", "last_name"=>"Landi", "scopus_author_id"=>"7005278728"}, {"first_name"=>"Tatiana", "last_name"=>"Dracheva", "scopus_author_id"=>"6602490982"}, {"first_name"=>"Melissa", "last_name"=>"Rotunno", "scopus_author_id"=>"24399869700"}, {"first_name"=>"Jonine D.", "last_name"=>"Figueroa", "scopus_author_id"=>"16021981100"}, {"first_name"=>"Huaitian", "last_name"=>"Liu", "scopus_author_id"=>"37079916600"}, {"first_name"=>"Abhijit", "last_name"=>"Dasgupta", "scopus_author_id"=>"56014959600"}, {"first_name"=>"Felecia E.", "last_name"=>"Mann", "scopus_author_id"=>"15765504000"}, {"first_name"=>"Junya", "last_name"=>"Fukuoka", "scopus_author_id"=>"6603028499"}, {"first_name"=>"Megan", "last_name"=>"Hames", "scopus_author_id"=>"16238608300"}, {"first_name"=>"Andrew W.", "last_name"=>"Bergen", "scopus_author_id"=>"7005186326"}, {"first_name"=>"Sharon E.", "last_name"=>"Murphy", "scopus_author_id"=>"7402779008"}, {"first_name"=>"Ping", "last_name"=>"Yang", "scopus_author_id"=>"56437082300"}, {"first_name"=>"Angela C.", "last_name"=>"Pesatori", "scopus_author_id"=>"7003638542"}, {"first_name"=>"Dario", "last_name"=>"Consonni", "scopus_author_id"=>"7004588960"}, {"first_name"=>"Pier Alberto", "last_name"=>"Bertazzi", "scopus_author_id"=>"24491461800"}, {"first_name"=>"Sholom", "last_name"=>"Wacholder", "scopus_author_id"=>"7005906464"}, {"first_name"=>"Joanna H.", "last_name"=>"Shih", "scopus_author_id"=>"7201813210"}, {"first_name"=>"Neil E.", "last_name"=>"Caporaso", "scopus_author_id"=>"35376837100"}, {"first_name"=>"Jin", "last_name"=>"Jen", "scopus_author_id"=>"7101875673"}], "year"=>2008, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-45749140422", "sgr"=>"45749140422", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0001651", "pmid"=>"18297132", "isbn"=>"1932-6203", "pui"=>"351865456"}, "id"=>"ba77b3a6-df1b-36c3-858a-5a2fff048b2d", "abstract"=>"BACKGROUND: Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.\\n\\nCONCLUSIONS/SIGNIFICANCE: Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.", "link"=>"http://www.mendeley.com/research/gene-expression-signature-cigarette-smoking-role-lung-adenocarcinoma-development-survival-2", "reader_count"=>100, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>6, "Researcher"=>29, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>7, "Student > Master"=>12, "Other"=>4, "Student > Bachelor"=>9, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>6, "Researcher"=>29, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>7, "Student > Master"=>12, "Other"=>4, "Student > Bachelor"=>9, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Agricultural and Biological Sciences"=>43, "Chemistry"=>1, "Computer Science"=>10, "Energy"=>1, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>10, "Mathematics"=>3, "Medicine and Dentistry"=>15, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>3, "Social Sciences"=>1, "Immunology and Microbiology"=>2, "Environmental Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>15}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>3}, "Mathematics"=>{"Mathematics"=>3}, "Unspecified"=>{"Unspecified"=>8}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Environmental Science"=>{"Environmental Science"=>1}, "Engineering"=>{"Engineering"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Energy"=>{"Energy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>43}, "Computer Science"=>{"Computer Science"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}}, "reader_count_by_country"=>{"Pakistan"=>1, "United States"=>5, "Japan"=>1, "United Kingdom"=>1, "Slovenia"=>1, "Germany"=>2, "Spain"=>2}, "group_count"=>6}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/936757"], "description"=>"a<p>Relative Risk of death. Analysis based on 54 current and former smokers using 262 probes from the Current/Never smoking comparisons (98 down- and 64 up-regulated probes from T and 75 down- and 28 up-regulated probes from NT, minus 3 overlapping probes in T and NT); models adjusted for tumor stage, sex, and smoking status</p>b<p>95% Confidence Interval</p>c<p>T = Lung adenocarcinoma samples of any stage (N = 42); NT = Non-Tumor tissue samples (N = 34)</p>", "links"=>[], "tags"=>["smokers", "differentiating", "non-tumor", "samples"], "article_id"=>607187, "categories"=>["Genetics", "Cancer", "Biotechnology"], "users"=>["Maria Teresa Landi", "Tatiana Dracheva", "Melissa Rotunno", "Jonine D. Figueroa", "Huaitian Liu", "Abhijit Dasgupta", "Felecia E. Mann", "Junya Fukuoka", "Megan Hames", "Andrew W. Bergen", "Sharon E. Murphy", "Ping Yang", "Angela C. Pesatori", "Dario Consonni", "Pier Alberto Bertazzi", "Sholom Wacholder", "Joanna H. Shih", "Neil E. Caporaso", "Jin Jen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0001651.t003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mortality_risk_in_smokers_for_gene_expression_differentiating_current_from_never_smokers_C_N_in_lung_tumor_and_non_tumor_tissue_samples_p_lt_0_01_/607187", "title"=>"Mortality risk in smokers for gene expression differentiating current from never smokers (C/N) in lung tumor and non-tumor tissue samples (p<0.01)", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-02-20 01:59:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/936564"], "description"=>"<p>Left: Running Enrichment Score (y axis) is calculated by walking down the entire list of probes from Affymetrix HG-U133A chip (numbered from 1 to 22,283 in the x axis) ordered by the ANOVA coefficients divided by the standard error values from the Former/Never (F/N) smoking comparison. This running-sum statistic increases when a given probe is in the Current/Never (C/N) Gene Set of interest and decreases when the probe is not in the C/N Gene Set, with the magnitude of increment depending on the strength of the correlation between the probe and the F/N comparison. The Enrichment Score (ES) is the maximum deviation of the Running Enrichment Score from zero encountered in the random walk and reflects the degree to which the Gene Set is overrepresented at the extremes (top or bottom) of the entire ranked probe list. We report results for two different C/N Gene Sets: on the top, the 64 up-regulated probes, with ES = 0.87 and, on the bottom, the 98 down-regulated probes, with ES = −0.90. A leading edge subset of the Gene Set is defined as those probes in the Gene Set that appear in the probes ranked list at, or before, the point where the running sum reaches its maximum deviation from zero. The leading edge for the Gene Set of the C/N up-regulated probes contains 58 probes over 64 and the leading edge for the Gene Set of down-regulated probes contains 90 over 98 probes. This confirms that among the 64 up-regulated probes from the C/N comparison, 58 are also found in the F/N comparison; and among the 98 down-regulated probes from the C/N comparison, 90 are also found in the F/N comparison. Right: distributions of ES values created using a permutation procedure for (top) the Gene Set of up-regulated probes in C/N and (bottom) the Gene Set of down-regulated probes in C/N. These distributions are used to calculate the statistical significance (nominal p-value) of the observed ES values (p-value<0.002 in both cases).</p>", "links"=>[], "tags"=>["differentiating", "smokers", "enrichment"], "article_id"=>606981, "categories"=>["Genetics", "Cancer", "Biotechnology"], "users"=>["Maria Teresa Landi", "Tatiana Dracheva", "Melissa Rotunno", "Jonine D. Figueroa", "Huaitian Liu", "Abhijit Dasgupta", "Felecia E. Mann", "Junya Fukuoka", "Megan Hames", "Andrew W. Bergen", "Sharon E. Murphy", "Ping Yang", "Angela C. Pesatori", "Dario Consonni", "Pier Alberto Bertazzi", "Sholom Wacholder", "Joanna H. Shih", "Neil E. Caporaso", "Jin Jen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0001651.g001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_gene_expression_differentiating_current_from_never_smokers_C_N_and_gene_expression_differentiating_former_from_never_smokers_F_N_in_early_stage_tumor_tissue_T_using_Gene_Set_Enrichment_Analysis_GSEA_/606981", "title"=>"Comparison of gene expression differentiating current from never smokers (C/N) and gene expression differentiating former from never smokers (F/N) in early stage tumor tissue (T) using Gene Set Enrichment Analysis (GSEA).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-02-20 01:56:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/936812"], "description"=>"†<p>Probe selection restricted to estimates with p<0.001 and fold-change >1.5 or <0.6667, and within the most inclusive category of genes with p≤0.001 in the GoMiner analysis (GO ID 7049, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001651#pone.0001651.s002\" target=\"_blank\">Appendix S2D</a>).</p>*<p>Genes involved in the mitotic spindle formation. The double line separates up-regulated and down-regulated probes.</p>", "links"=>[], "tags"=>["genes", "differentiating", "smokers", "corresponding", "smoker", "paired"], "article_id"=>607238, "categories"=>["Genetics", "Cancer", "Biotechnology"], "users"=>["Maria Teresa Landi", "Tatiana Dracheva", "Melissa Rotunno", "Jonine D. Figueroa", "Huaitian Liu", "Abhijit Dasgupta", "Felecia E. Mann", "Junya Fukuoka", "Megan Hames", "Andrew W. Bergen", "Sharon E. Murphy", "Ping Yang", "Angela C. Pesatori", "Dario Consonni", "Pier Alberto Bertazzi", "Sholom Wacholder", "Joanna H. Shih", "Neil E. Caporaso", "Jin Jen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0001651.t002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_cycle_genes_differentiating_current_from_never_smokers_C_N_in_the_early_stage_tumor_T_tissue_samples_and_corresponding_values_in_the_former_never_smoker_F_N_and_in_the_smokers_paired_tumor_non_tumor_tissue_T_NT_comparisons_/607238", "title"=>"Cell cycle genes differentiating current from never smokers (C/N) in the early stage tumor (T) tissue samples, and corresponding values in the former/never smoker (F/N) and in the smokers' paired tumor/non-tumor tissue (T/NT) comparisons.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-02-20 02:00:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/936872"], "description"=>"a<p>Validation in 68 samples used also for microarray analysis;</p>b<p>Confirmation in 40 independent samples from EAGLE and Mayo Clinic</p>c<p>C/N = Current/Never smoking comparison</p>", "links"=>[], "tags"=>["Real-time", "pcr", "validation", "microarray", "genes", "differentiating", "smokers", "non-tumor", "samples", "confirmation"], "article_id"=>607286, "categories"=>["Genetics", "Cancer", "Biotechnology"], "users"=>["Maria Teresa Landi", "Tatiana Dracheva", "Melissa Rotunno", "Jonine D. Figueroa", "Huaitian Liu", "Abhijit Dasgupta", "Felecia E. Mann", "Junya Fukuoka", "Megan Hames", "Andrew W. Bergen", "Sharon E. Murphy", "Ping Yang", "Angela C. Pesatori", "Dario Consonni", "Pier Alberto Bertazzi", "Sholom Wacholder", "Joanna H. Shih", "Neil E. Caporaso", "Jin Jen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0001651.t004", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_Real_Time_PCR_validation_of_microarray_results_of_genes_differentiating_current_from_never_smokers_C_N_in_tumor_T_and_non_tumor_NT_tissue_samples_and_confirmation_in_independent_samples_/607286", "title"=>"Quantitative Real-Time PCR validation of microarray results of genes differentiating current from never smokers (C/N) in tumor (T) and non-tumor (NT) tissue samples and confirmation in independent samples", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-02-20 02:01:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/461877", "https://ndownloader.figshare.com/files/461937", "https://ndownloader.figshare.com/files/462043", "https://ndownloader.figshare.com/files/462101", "https://ndownloader.figshare.com/files/462206"], "description"=>"<div><h3>Background</h3><p>Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.</p><h3>Methodology/Principal Findings</h3><p>We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors <u>and</u> early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.</p><h3>Conclusions/Significance</h3><p>Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.</p></div>", "links"=>[], "tags"=>["smoking", "adenocarcinoma"], "article_id"=>151019, "categories"=>["Genetics", "Cancer", "Biotechnology"], "users"=>["Maria Teresa Landi", "Tatiana Dracheva", "Melissa Rotunno", "Jonine D. Figueroa", "Huaitian Liu", "Abhijit Dasgupta", "Felecia E. Mann", "Junya Fukuoka", "Megan Hames", "Andrew W. Bergen", "Sharon E. Murphy", "Ping Yang", "Angela C. Pesatori", "Dario Consonni", "Pier Alberto Bertazzi", "Sholom Wacholder", "Joanna H. Shih", "Neil E. Caporaso", "Jin Jen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0001651.s001", "https://dx.doi.org/10.1371/journal.pone.0001651.s002", "https://dx.doi.org/10.1371/journal.pone.0001651.s003", "https://dx.doi.org/10.1371/journal.pone.0001651.s004", "https://dx.doi.org/10.1371/journal.pone.0001651.s005"], "stats"=>{"downloads"=>31, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Gene_Expression_Signature_of_Cigarette_Smoking_and_Its_Role_in_Lung_Adenocarcinoma_Development_and_Survival/151019", "title"=>"Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-02-20 00:16:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/936710"], "description"=>"a<p>FDR = False Discovery Rate <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001651#pone.0001651-Benjamini1\" target=\"_blank\">[2]</a></p>", "links"=>[], "tags"=>["probes", "genes", "differentiating", "smokers", "samples", "non-tumor"], "article_id"=>607133, "categories"=>["Genetics", "Cancer", "Biotechnology"], "users"=>["Maria Teresa Landi", "Tatiana Dracheva", "Melissa Rotunno", "Jonine D. Figueroa", "Huaitian Liu", "Abhijit Dasgupta", "Felecia E. Mann", "Junya Fukuoka", "Megan Hames", "Andrew W. Bergen", "Sharon E. Murphy", "Ping Yang", "Angela C. Pesatori", "Dario Consonni", "Pier Alberto Bertazzi", "Sholom Wacholder", "Joanna H. Shih", "Neil E. Caporaso", "Jin Jen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0001651.t001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Number_of_probes_and_genes_differentiating_current_from_never_smokers_C_N_and_former_from_never_smokers_F_N_in_all_tumor_samples_early_stage_tumor_samples_T_and_all_non_tumor_NT_tissue_samples_/607133", "title"=>"Number of probes and genes differentiating current from never smokers (C/N) and former from never smokers (F/N) in all tumor samples, early stage tumor samples (T), and all non-tumor (NT) tissue samples.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-02-20 01:58:53"}

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Relative Metric

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