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 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 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 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.
Keck, MK; Zuo, Z; Khattri, A; Stricker, TP; Brown, CD; Imanguli, M; Rieke, D; Endhardt, K; Fang, P; Brägelmann, J; DeBoer, R; El-Dinali, M; Aktolga, S; Lei, Z; Tan, P; Rozen, SG; Salgia, R; Weichselbaum, RR; Lingen, MW; Story, MD; Ang, KK; Cohen, EEW; White, KP; Vokes, EE; Seiwert, TY
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