Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes

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 human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV⁺ tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several sub-type-specifi c, 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 subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes. Conclusion: Our fi ve-subtype classifi cation provides a comprehensive overview of HPV⁺ as well as HPV^- HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC. Clin Cancer Res.