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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common nonskin cancer worldwide with an annual inci-Note: Supplementary data for this article are available at Clinical Cancer Research Online.M.K
Our five-subtype classification provides a comprehensive overview of HPVþ as well as HPVÀ HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC
We identify five Head and neck cancer (HNC) subtypes, including two distinct human papillomavirus (HPV) subtypes with differential biology across multiple HNC cohorts, and show validity of subtypes and associated biology across all currently available HNC datasets, including The Cancer Genome Atlas (TCGA) HNC cohort: In particular, we report (i) an immune phenotype present in a group of HNC tumors independent of HPV status and (ii) a group with non– HPV-associated tumors showing a prominent HER-driven phenotype as well as hypoxia, which are candidate biomarkers for respective therapies (e.g., PD-1, EGFR/HER, or hypoxiatargeting agents)
Summary
Our aim was to select at least 100 cases to be able to perform consensus clustering later. We aimed to further investigate these aberrant regions by scanning 72 additional genes within copy number altered regions in 55 of the samples
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