Since PROM1 promoter hypermethylation seems to be a general methylation signature in HNSCC regardless of anatomical location and HPV status, prospective clinical trials with large sample sizes and correlative studies analyzing PROM1 promoter methylation status are warranted to further explore the potential role of dual biomarkers in any subgroups of HNSCC. The gene discussed is PROM1; the disease is head and neck squamous cell carcinoma.