Disease-specific N-glycopeptides in serum of patients with oral squamous cell carcinoma

The incidence of oropharyngeal cancers is increasing due to human papilloma virus (HPV); however, this phenomenon does not explain the rising incidence of oral cancers, for which the reason remains unknown. These cancers are typically diagnosed at an advanced stage, which adversely affects the prognosis. Improved methods for early detection, such as blood-based biomarkers, could significantly improve patient outcomes. We investigated quantitative and qualitative differences in serum protein N-glycosylation between patients with oral squamous cell carcinoma (OSCC) and healthy controls using label-free mass spectrometry-based proteomics and N-glycopeptidomics. Twenty-five N-glycopeptides from seven different proteins were identified, all glycoforms associated with abundant serum proteins. While protein expression differences between OSCC and controls were modest (≤ 2-fold), certain glycoforms showed pronounced changes, with fold differences ranging from 7 to 33, highlighting their role as potential biomarkers. Importantly, the glycosylation patterns observed in OSCC were distinct from those previously reported in oropharyngeal cancer, suggesting a level of disease specificity. These observations support the future potential of N-glycosylation changes to serve as cancer-specific biomarkers.