Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. Experimental Design: Here we use gene expression based consensus clustering, copy number profiling, and HPV-status on a clinically homogenous cohort of 134 locoregionally-advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 931 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics. Results: We identified five subtypes of HNSCC including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8+ lymphocytes characterizes this inflamed/mesenchymal subtypes - independent of HPV status. Compared to other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER-ligands and absence of EGFR/HER-ligand expression. By contrast the Basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype driven by multiple HER ligands, as well as strong hypoxic differentiation not seen in other subtypes. Conclusion: Our five-subtype classification provides a comprehensive overview of HPV(+) as well as HPV(-) HNSCC biology with significant translational implications for biomarker development and personalized care for HNSCC patients.
- Received October 14, 2014.
- Accepted November 7, 2014.
- Copyright © 2014, American Association for Cancer Research.