PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis

Abstract

Oral tongue squamous cell carcinomas (OTSCCs) have an increasing incidence in young patients, and many have an aggressive course of disease. The objective of this study was to identify candidate prognostic protein markers associated with early-onset OTSCC. We performed an exploratory screening for differential protein expression in younger (≤45 years) versus older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n = 97). Expression of candidate markers was then validated in an independent Austrian OTSCC patient group (n = 34) by immunohistochemistry. Kaplan–Meier survival estimates were computed, and genomic and mRNA enrichment in silico analyses were performed. Overexpression of protein kinase C alpha (PRKCA) was significantly more frequent among young patients of both the TCGA (p = 0.0001) and the Austrian cohort (p = 0.02), associated with a negative anamnesis for alcohol consumption (p = 0.009) and tobacco smoking (p = 0.02) and poorer overall survival (univariate p = 0.02, multivariate p< 0.01). Within the young subgroup, both overall and disease-free survival were significantly decreased in patients with PRKCA overexpression (both p < 0.001). TCGA mRNA enrichment analysis revealed 332 mRNAs with significant differential expression in PRKCA-upregulated versus PRKCA-downregulated OTSCC (all FDR ≤ 0.01). Our findings suggest that PRKCA overexpression may be a hallmark of a novel molecular subtype of early-onset alcohol- and tobacco-negative high-risk OTSCC. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA-overexpressing OTSCC.

Identification of Molecular Subtypes and Prognostic Characteristics of Adrenocortical Carcinoma Based on Unsupervised Clustering

“…Consequently, these processes collectively contribute to facilitating tumor progression. Regarding the prognosis, the presence of PRKCA in oral tongue squamous cell carcinomas (OTSCC) was linked to a lack of smoking and alcohol consumption history, leading to reduced OS [34]. PRKCA overexpression has been associated with reduced survival outcomes not only in ACC patients but also in lung adenocarcinoma [35].…”

A Signature of N6-methyladenosine Regulator-Related Genes Predicts Prognoses and Immune Responses for Head and Neck Squamous Cell Carcinoma

“…For example, the following six genes are located at the center of the key protein interaction network: PRKCA, MAP2K7, VDAC1, FZD6, SQSTM1, and CYCS. PRKCA is overexpressed in oral tongue squamous cell carcinoma and has been associated with poor prognosis (33). MAP2K7A has been used as a candidate tumor suppressor in gastric cancer (34) and T-cell acute lymphoblastic leukemia (35,36), and has demonstrated the potential to be used as a prognostic biomarker for prostate cancer (37).…”

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

“…PKCα upregulation is associated with a negative history of alcohol and tobacco consumption. Both overall survival and disease-free survival are impaired in young patients with PKCα overexpression [ 174 ]. Furthermore, CC-chemokine receptor 7 and PKCα overexpression in HNSCC are significantly correlated with both cervical lymph node metastasis and clinical stage [ 175 ].…”

“…PKCα overexpression was associated with poor overall and disease-free survival as well as with no alcohol and tobacco consumption. These results indicate that PKCα overexpression may be a novel diagnostic molecular marker for early-onset alcohol- and tobacco-negative high-risk OTSCC [ 174 ].…”