Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Figure 1. Gene Expression Subtypes in Head and Neck Squamous Cell Carcinoma.

Heatmaps of the expression values of the 840 classifier genes (A) and select genes associated with HNSCC (B) for each of the expression subtypes. Validation heatmaps of the centroid-based distances between the centroids of the expression subtypes in the current study and those from Chung et al. (C) and the LUSC subtypes of Wilkerson et al. (D).

Figure 2. Copy Number Gains and Losses in the Expression Subtypes.

Plots of the mean copy number values in the HNSCC expression subtypes after smoothing and outlier removal, both genome-wide (A) and for specific chromosomes or regions of interest (B).

Figure 3. Average Gene Expression and Copy Number by Expression Subtype.

Mean gene-specific copy number and gene expression values in the HNSCC expression subtypes and normal tonsil samples (NL) for genes in the 3q amplicon.

Figure 4. Recurrence-Free Survival in Expression Subtypes.

Kaplan-Meier plots and Log-Rank Test p-values comparing recurrence-free survival times in all expression subtypes (A), HPV+ vs. HPV− subjects (B), all expression subtypes in HPV− subjects (C), and AT vs. non-AT in HPV− subjects (D). Statistical significance was assessed using the Log Rank Test.