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Abstract
Oral Tongue Squamous cell carcinoma (OTSCC), the most frequently affected oral cancer sub-site, is associated with a poor therapeutic outcome and survival despite aggressive multi- modality management. Till date, there are no established biomarkers to indicate prognosis and outcome in patients presenting with tongue cancer. There is an urgent need for reliable molecular prognostic factors to enable identification of patients with high risk of recurrence and treatment failure in OTSCC management. In the current study, we present the meta-analysis of OTSCC microarray based gene expression profiles, deriving a comprehensive molecular portrait of tongue cancer biology, showing the relevant genes and pathways which can be pursued further to derive novel, tailored therapeutics as well as for prognostication. We have studied 5 gene expression profiling data sets available on exclusively oral tongue subsite comprising of sample size; n = 190, consisting of 111 tumors and 79 normals. The meta- analysis results showed 2405 genes differentially regulated comparing OTSCC tumor and normal. The top up regulated genes were found to be involved in Extracellular matrix degradation (ECM) and Epithelial to mesenchymal transition (EMT) pathways. The top down regulated genes were found to be involved in detoxication pathways. We validated the results in clinical samples (n = 206), comprising of histologically normals (n = 10), prospective (n = 29) and retrospective (n = 167) OTSCC by evaluating MMP9 and E-cadherin gene expression by qPCR and immunohistochemistry. Consistent with meta-analysis results, MMP9 mRNA expression was significantly up regulated in OTSCC primary tumors compared to normals. MMP9 protein over expression was found to be a significant predictor of poor prognosis, disease recurrence and poor Disease Free Survival (DFS) in OTSCC patients. Analysis by univariate and multivariate Cox proportional hazard model showed patients with loss of E-cadherin expression in OTSCC tumors having a poorer DFS (HR = 1.566; P value = 0.045) and poorer Overall Survival (OS) (HR = 1.224; P value = 0.003) respectively. Combined over-expression of MMP9 and loss of E-cadherin membrane positivity in the invasive tumor front (ITF) of OTSCC had a significant association with poorer DFS (Log Rank = 16.040; P value = 0.001). These results suggest that along with known clinical indicators of prognosis like occult node positivity, assessment of MMP9 and E-cadherin expression at ITF can be useful to identify patients at high risk and requiring a more intensive treatment strategy for OTSCC. Meta-analysis study of gene expression profiles indicates that OTSCC is a disease of ECM degradation leading to activated EMT processes implying the aggressive nature of the disease. The triggers for these processes should be studied further. Newer clinical application with agents that can inhibit the mediators of ECM degradation may be a key to achieving clinical control of invasion and metastasis of OTSCC.
Highlights
Oral Tongue Squamous Cell Carcinoma (OTSCC) is regarded as a biologically unique entity compared to cancers occurring in the other oral sub-sites
Class comparison by BRB array tools gave a list of 434 differentially expressed genes (DEG), of which 194 were up-regulated and 241 were down-regulated. (S1 Table) The advantage of this method is that the actual fold-change of gene expression and the consistencies of deregulation across the 5 datasets were taken into consideration, which helped us to narrow down on genes that are both biologically and statistically significant
Current study indicates that Extracellular matrix degradation (ECM) is severely compromised and Epithelial to mesenchymal transition (EMT) processes are activated in OTSCC
Summary
Oral Tongue Squamous Cell Carcinoma (OTSCC) is regarded as a biologically unique entity compared to cancers occurring in the other oral sub-sites. The trend in epidemiology of oral cancer in Asia in the past decade (2000–2012) shows OTSCC as the most frequently affected oral sub-site. [8] Most often we have findings that are not reproducible across studies due to data perturbations of individual studies, improper validations, and insufficient control of false positives. Despite these obstacles, several groups have successfully gleaned important insights from the focused comparison of disparate microarray results. Several groups have successfully gleaned important insights from the focused comparison of disparate microarray results. [9, 10] Many of the limitations can be mitigated by the use of standard reporting methods, together with careful application of largescale meta-analysis techniques
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