Dogan S, et al. - Among 157 cases of primary resected oropharyngeal squamous cell carcinoma (OPSCC), including HPV-positive (HPV-P) and HPV-negative (HPV-N) OPSCC cases, researchers assessed the link between genetic alterations and long-term outcome. They found that NOTCH1-mutated HPV-P and SOX2-amplified HPV-N cases had a poorer overall survival. In HPV-P, chromosomal arm gains in 8p and 8q, and 16q loss were more common, while more frequently they detected 9p, 18q and 21q losses in HPV-N OPSCC. In HPV-P tumors, potentially functional JAK3, MYC and EP300 intragenic deletions were detected. In HPV-N tumors, they found FOXP1, CDKN2A, CCND1 and RUNX1 intragenic deletions and one FGFR3 inversion. In NOTCH1/3/4 (39%), PIK3CA, FAT1, and TERT, recurrent mutations were present in HPV-N/TP53-wild type OPSCC. The outcome in OPSCC was determined by HPV status, tumor subsite and smoking. On the basis of mutational signature, namely NOTCH1 and SOX2 mutation status, a further refined risk-stratification can be achieved.