title: Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation.
abstract: OBJECTIVE
  Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.
  
  
  METHODS
  Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).
  
  
  RESULTS
  The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.
  
  
  CONCLUSIONS
  Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.
authors.affiliation: Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.forename: Miriam
authors.initials: M
authors.lastname: Lohr
authors.forename: Birte
authors.initials: B
authors.lastname: Hellwig
authors.forename: Lars
authors.initials: L
authors.lastname: Holmberg
authors.forename: Mats
authors.initials: M
authors.lastname: Lambe
authors.forename: Anders
authors.initials: A
authors.lastname: Berglund
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: André
authors.initials: A
authors.lastname: König
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Fernandes
authors.forename: Mats
authors.initials: M
authors.lastname: Karlsson
authors.forename: Gisela
authors.initials: G
authors.lastname: Helenius
authors.forename: Christina
authors.initials: C
authors.lastname: Karlsson
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins