Diagnostic value of cyclin-dependent kinase/cyclin-dependent kinase inhibitor expression ratios as biomarkers of locoregional and hematogenous dissemination risks in oral squamous cell carcinoma.

The aim of the present study was to investigate the diagnostic value of cell cycle-related genes in oral squamous cell carcinoma (OSCC) by examining the expression of the following genes in 77 OSCC tissues by quantitative polymerase chain reaction: Cyclin genes (CCNA1, CCND1, CCND2 and CCNE1), cyclin-dependent kinase (CDK) genes (CDK1, CDK2 and CDK4), CDK inhibitor genes (CDKN2A, CDKN1A, CDKN1B and CDKN1C), and integrin and associated genes that we previously reported (ITGA3, ITGB4, CD9 and JUP). The expression ratios of 66 combinations of the 11 cell cycle-related genes were analyzed to examine their associations with major clinical events using Mann-Whitney U and log-rank tests. Three expression ratios (CDK1/CDKN1B, CDK2/CDKN1A and CCNE1/CDK2) showed associations on univariate analyses and their diagnostic value was re-analyzed with integrin gene expression biomarkers (ITGA3/CD9 and ITGB4/JUP) using the Cox proportional hazards model and Kaplan-Meier estimates. Lymph node metastasis occurred in >90% of double-positive cases (high-ITGA3/CD9 and high-CDK1/CDKN1B) irrespective of tumor size (P<0.0001). Primary site recurrence was found in >30% of double-positive cases (high-ITGA3/CD9 and high-CDK2/CDKN1A) with tumors >20 mm (P=0.003). Triple-positive (high-ITGB4/JUP, high-ITGA3/CD9 and high-CDK2/CDKN1A) was associated with distant metastasis (P<0.0001), but not with other clinical parameters. Disease-specific death occurred in 55% of double-positive cases (high-ITGA3/CD9 and high-CDK2/CDKN1A) (P<0.0001) and a positive surgical margin was a significant factor for fatality in these cases. Reliable prediction of locoregional and hematogenous dissemination risks in OSCC using the four CDK and integrin gene expression ratios is a promising biomarker system. Clinical use of these parameters may improve the control rate with the use of new therapeutic strategies.