title: Integrated molecular portrait of non-small cell lung cancers.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC.
  
  
  METHODS
  Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC.
  
  
  RESULTS
  At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1 and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944.
  
  
  CONCLUSIONS
  Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. yudi.pawitan@ki.se.
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authors.lastname: Lazar
authors.forename: Chen
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authors.forename: Cedric
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authors.forename: Joost
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authors.lastname: van den Oord
authors.forename: Zsofia
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authors.forename: Justine
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authors.forename: Bastien
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authors.forename: Guillaume
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authors.forename: Hugues
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authors.forename: Stefano
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authors.lastname: Calza
authors.forename: Johanna
authors.initials: J
authors.lastname: Hasmats
authors.forename: Joakim
authors.initials: J
authors.lastname: Lundeberg
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Philippe
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authors.forename: Fabienne
authors.initials: F
authors.lastname: Dufour
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.forename: Rudolf
authors.initials: R
authors.lastname: Napieralski
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.forename: Philippe
authors.initials: P
authors.lastname: Girard
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Yudi
authors.initials: Y
authors.lastname: Pawitan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger