Genomic profiling of oropharyngeal squamous cell carcinoma by human papillomavirus status in an Asian cohort: the TCOG T1322 registry study

Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) are biologically distinct entities with different clinical behaviors and therapeutic responses. However, genomic studies of OPSCC have largely focused on Western populations, and the molecular landscape in Asian patients remains incompletely defined. This study characterized genomic alterations, mutational signatures, and therapeutic actionability of OPSCC according to HPV status in an Asian cohort. This multicenter tissue-based next-generation sequencing registry study (TCOG T1322; NCT05522881, registered on August 31, 2022) enrolled patients with pathologically confirmed head and neck squamous cell carcinoma in Taiwan. Tumor samples underwent comprehensive genomic profiling using a 440-gene targeted panel. Tumor genomic alterations, pathway dysregulation, mutational signatures, tumor mutational burden (TMB), and therapeutic actionability were analyzed by p16-defined HPV status. Among 290 patients with OPSCC, 190 had HPV-positive and 100 had HPV-negative tumors. HPV-positive OPSCC frequently harbored alterations in PIK3CA (37%), BCL6 (14%), and immune checkpoint ligand amplifications CD274/PDCD1LG2 (6%). HPV-negative tumors were enriched for TP53 mutations (89%), CDKN2A deletions (34%), FAT1 alterations (33%), and CCND1 amplifications (30%). HPV-negative tumors showed greater dysregulation of cell cycle, differentiation, and oxidative stress pathways, whereas HPV-positive tumors were enriched for immune-related alterations. APOBEC-associated single-base-substitution (SBS) signatures SBS2/SBS13 predominated in HPV-positive tumors, while SBS5/SBS16 were more common in HPV-negative tumors. Among HPV-positive tumors, smokers demonstrated higher BCL6 and TP53 alterations and distinct mutational patterns. HPV-positive tumors also had higher TMB and greater prevalence of TMB-high status. OPSCC exhibits distinct p16-defined genomic profiles in this Asian cohort, providing insights into its biological heterogeneity and identifying potential translational therapeutic targets for further investigation.