PRKCA overexpression is frequent in young oral tongue squamous cell carcinoma patients and is associated with poor prognosis

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Abstract Oral tongue squamous cell carcinoma (OTSCC) have an increasing incidence in young patients and many have an aggressive course of disease. The molecular mechanisms for this increase are unknown and biologic markers to identify high risk patients are lacking. In an unbiased data screening for differential protein expression of younger (≤45 years) and older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n=98) we identified Protein kinase C alpha (PRKCA), to be significantly more frequently overexpressed in younger versus older patients (p=0.0001). These results were experimentally validated and confirmed in an independent Austrian OTSCC patient sample (n=34) by immunohistochemistry (p=0.0026). PRKCA upregulation was associated with negative anamnesis for alcohol consumption (p=0.009) and tobacco smoking (p=0.02). Univariate and multivariate analysis of overall survival (OS) and disease-free survival (DFS) showed a significantly worse prognosis in patients with tumors overexpressing PRKCA regarding OS (univariate p= 0.04, multivariate p< 0.01). In the young subgroup both OS and DFS were significantly decreased in PRKCA positive patients (both p< 0.001). TCGA messenger RNA enrichment analysis showed 24 mRNAs with significant differential expression in PRKCA positive OTSCC (all p≤ 0.05 after Benjamini-Hochberg correction). Our findings suggest the potential existence of a distinct molecular subtype of alcohol and tobacco negative, high risk OTSCC in a significant proportion of early onset individuals. Our findings warrant validation in additional OTSCC patient cohorts. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA overexpressing OTSCC.

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