title: Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types.
abstract: OBJECTIVE
  Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous, and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant.
  
  
  METHODS
  Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods.
  
  
  RESULTS
  Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P < 0.001). The primitive subtype had the worst survival outcome (P < 0.05) and is an independent predictor of survival (P < 0.05). Tumor differentiation and patient sex were associated with subtype. The expression profiles of the subtypes contained distinct biological processes (primitive: proliferation; classical: xenobiotic metabolism; secretory: immune response; basal: cell adhesion) and suggested distinct pharmacologic interventions. Comparison with lung model systems revealed distinct subtype to cell type correspondence.
  
  
  CONCLUSIONS
  Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Yin
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Michele C
authors.initials: MC
authors.lastname: Hayward
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cabanski
authors.forename: Kenneth
authors.initials: K
authors.lastname: Muldrew
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Alden M
authors.initials: AM
authors.lastname: Parsons
authors.forename: William K
authors.initials: WK
authors.lastname: Funkhouser
authors.forename: Carrie B
authors.initials: CB
authors.lastname: Lee
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: Leigh
authors.initials: L
authors.lastname: Thorne
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics*; D015203:Reproducibility of Results; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D012333:RNA, Messenger