Stepp WH, et al. - Experts evaluated whether a tumour-specific genetic signature existed for node-negative vs node-positive human papillomavirus (HPV) 16–positive/p16-positive oropharyngeal squamous cell carcinomas (OPSCCs). Treatment of many HPV-16 and p16-positive tumours was done as “lower-risk,” but at the biological level, they did not have similar genetic compositions. Physicians could be guided toward alternative or more aggressive therapies by the identification of subgroups with unique expression patterns. The larger biological characteristics of a tumour could be a better prognostic biomarker, as suggested by unguided clustering.