title: Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts.
abstract: OBJECTIVE
  Published reports suggest that DNA microarrays identify clinically meaningful subtypes of lung adenocarcinomas not recognizable by other routine tests. This report is an investigation of the reproducibility of the reported tumor subtypes.
  
  
  METHODS
  Three independent cohorts of patients with lung cancer were evaluated using a variety of DNA microarray assays. Using the integrative correlations method, a subset of genes was selected, the reliability of which was acceptable across the different DNA microarray platforms. Tumor subtypes were selected using consensus clustering and genes distinguishing subtypes were identified using the weighted difference statistic. Gene lists were compared across cohorts using centroids and gene set enrichment analysis.
  
  
  RESULTS
  Cohorts of 31, 72, and 128 adenocarcinomas were generated for a total of 231 microarrays, each with 2,553 reliable genes. Three adenocarcinoma subtypes were identified in each cohort. These were named bronchioid, squamoid, and magnoid according to their respective correlations with gene expression patterns from histologically defined bronchioalveolar carcinoma, squamous cell carcinoma, and large-cell carcinoma. Tumor subtypes were distinguishable by many hundreds of genes, and lists generated in one cohort were predictive of tumor subtypes in the two other cohorts. Tumor subtypes correlated with clinically relevant covariates, including stage-specific survival and metastatic pattern. Most notably, bronchioid tumors were correlated with improved survival in early-stage disease, whereas squamoid tumors were associated with better survival in advanced disease.
  
  
  CONCLUSIONS
  DNA microarray analysis of lung adenocarcinomas identified reproducible tumor subtypes which differ significantly in clinically important behaviors such as stage-specific survival.
authors.affiliation: University of North Carolina, Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC 27599-7295, USA. hayes@med.unc.edu
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naoki
authors.forename: Arindam
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Charles
authors.initials: C
authors.lastname: Perou
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D016019:Survival Analysis