Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes

TLDR

Current classification of head and neck squamous cell carcinomas based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. The study aimed to identify biologically distinct HNSCC subtypes by integrating gene expression clustering, copy number profiling, and HPV status across 938 tumors. Using consensus clustering of gene expression data, copy number analysis, and HPV testing on a clinically homogeneous cohort of 134 locoregionally advanced HNSCCs plus additional cohorts, the authors classified tumors into five subtypes. The analysis revealed five subtypes, including two distinct HPV subtypes with immune‑mesenchymal signatures, abundant CD8⁺ infiltration, and low EGFR/H.

Abstract

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.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 subtype-specific, translationally relevant characteristics.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.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 patients with HNSCC.