Lung Squamous Cell Carcinoma mRNA Expression Subtypes Are Reproducible, Clinically Important, and Correspond to Normal Cell Types

Abstract

Purpose: 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.Experimental Design: 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.

Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

“…Besides Sox2, p63 and Krt15, the known differentially expressed genes in each cancer type represented several functional groups, including metabolism, cell adhesion and migration, signal transduction and transcriptional regulation (Supplementary Table 1). Of the four previously identified gene expression signatures predictive of cytogenetic and molecular subtypes of human lung SCC (i.e., primitive, basal, secretory and classical), 5,36 SKIinduced tumors closely resembled the primitive subtype (Supplementary Table 2). Although an active MYC expression module is observed in many cancer types, 37 a set of genes reported to be induced by MYC activation showed no significant overlap with our data sets (Figure 6d).…”

Genomics of Squamous Cell Lung Cancer

“…Although there was heterogeneity in the functions of these hypermethylated genes, genes associated with the regulation of transcription, cytoskeletal organization, and cell cycle were overrepresented in these samples. Promoter hypermethylation was more frequently reported in the classical subtype by TCGA investigators [8,131]. Hypermethylation of the p16INK4a promoter (especially in smokers) has been discussed previously.…”

Immunological and classical subtypes of oral premalignant lesions

“…34,35 In our study, we applied these algorithms to build a classifier of OPL that we compared to an alternative classification method based on a 400 gene expression score using the ssGSEA tool. Scores based on gene expression and computed in individual samples have previously been proposed for classification purposes in biological samples e.g .…”

“…18,34 Gene expression values were gene median centered and the 2,500 most variable genes, using the median absolute deviation, were selected for clustering. We then used the ConsensusClusterPlus R package to cluster the OPL samples in an unbiased and unsupervised manner.…”