title: Triple-layer dissection of the lung adenocarcinoma transcriptome: regulation at the gene, transcript, and exon levels.
abstract: Lung adenocarcinoma is one of the most deadly human diseases. However, the molecular mechanisms underlying this disease, particularly RNA splicing, have remained underexplored. Here, we report a triple-level (gene-, transcript-, and exon-level) analysis of lung adenocarcinoma transcriptomes from 77 paired tumor and normal tissues, as well as an analysis pipeline to overcome genetic variability for accurate differentiation between tumor and normal tissues. We report three major results. First, more than 5,000 differentially expressed transcripts/exonic regions occur repeatedly in lung adenocarcinoma patients. These transcripts/exonic regions are enriched in nicotine metabolism and ribosomal functions in addition to the pathways enriched for differentially expressed genes (cell cycle, extracellular matrix receptor interaction, and axon guidance). Second, classification models based on rationally selected transcripts or exonic regions can reach accuracies of 0.93 to 1.00 in differentiating tumor from normal tissues. Of the 28 selected exonic regions, 26 regions correspond to alternative exons located in such regulators as tumor suppressor (GDF10), signal receptor (LYVE1), vascular-specific regulator (RASIP1), ubiquitination mediator (RNF5), and transcriptional repressor (TRIM27). Third, classification systems based on 13 to 14 differentially expressed genes yield accuracies near 100%. Genes selected by both detection methods include C16orf59, DAP3, ETV4, GABARAPL1, PPAR, RADIL, RSPO1, SERTM1, SRPK1, ST6GALNAC6, and TNXB. Our findings imply a multilayered lung adenocarcinoma regulome in which transcript-/exon-level regulation may be dissociated from gene-level regulation. Our described method may be used to identify potentially important genes/transcripts/exonic regions for the tumorigenesis of lung adenocarcinoma and to construct accurate tumor vs. normal classification systems for this disease.
authors.affiliation: Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu, Taiwan.
authors.forename: Min-Kung
authors.initials: MK
authors.lastname: Hsu
authors.affiliation: Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Wu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.|Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
authors.affiliation: Cloud Computing and System Integration Division, National Center for High-Performance Computing, Taichung, Taiwan.
authors.forename: Chang-Huain
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu, Taiwan.
authors.forename: Yeong-Shin
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu, Taiwan.|Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.|Department of Dentistry, China Medical University, Taichung, Taiwan.
authors.forename: Feng-Chi
authors.initials: FC
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D030541:Databases, Genetic; D005091:Exons; D020869:Gene Expression Profiling / Q000379:methods; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics*; D014162:Transfection
chemical_list: D017500:Adenovirus E1A Proteins; D014408:Biomarkers, Tumor; C079853:ETV4 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D000444:Aldehyde Dehydrogenase
keywords: alternative splicing; differential expression; lung adenocarcinoma; transcript-specific regulation; transcriptome analysis