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    2020-08-28

    r> Analysis of the combination marker Influenza Hemagglutinin HA Peptide showed that 14/17 (82%) of the recurrent patients showed high expression of more than one marker (3 patients showed high expression of all markers) as
    compared to 67% of the non-recurrent patients. Assessment of the markers indicated that 13/17 patients were CDK1highNQO1high in combination or with other markers (FKBP4, ERBB2, UBE2C). Similarly, 83% (10/12) deceased patients showed a high expression of > 1 marker as compared to 50% of the surviving patients (8/16). All the deceased patients showed high expression of either CDK1 and/or NQO1 in combination with other markers. Survival analysis indicated that among the 6 markers, CDK1 was significantly associated with the poor disease free survival (p < 0.05) and overall survival (p < 0.05), while NQO1 was significantly asso-ciated with poor overall survival (p < 0.05) (Fig. 5 E, F, G). Combined alterations in CDK1 and NQO1 was significantly associated with both poor overall and disease free survival (p < 0.05) (Fig. 5 H, I). A site-specific analysis indicated that in the tongue cancer patients, high median expression of RIT1 (2.18 vs 0.8, p = 0.02) and ERBB2 (1.02 vs 0.42, p = 0.05) was associated with poor survival, while in buccal 
    vasion and extra capsular spread) with the CDK1/NQO1 and prognosis of patients. The results showed that in the patient group with CDK1high
    Cox regression analysis (univariate) was performed to find out the independent risk factor/ hazard ratio of each marker and other clinical and pathological parameters; perineural invasion, extracapsular spread and risk habits having the highest hazard ratios (> 3.5). Among the molecular markers, CDK1 (HR: 3.77; p < 0.05) NQO1 (HR: 2), RIT1 (HR: 1.53) and UBE2C (HR: 1.28) were independent risk factors for disease free survival. Assessment with overall survival indicated that while angiolymphatic invasion, T stage and differentiation were risk factors (HR > 1) among clinical parameters, high expression of CDK1 (HR: 4.94; p < 0.05), NQO1 (HR: 3.17) and RIT1 (HR: 1.45) also in-creased the risk in the patients (Table 7),
    4. Discussion
    Molecular markers along with the clinical features such as stage, margin status, angiolymphatic invasion have demonstrated prognostic ability in many solid tumors including head and neck (Adel et al., 2015; Jardim, Francisco, Gondak, Damascena, & Kowalski, 2015; Simple et al., 2015). Cancer stem cells, the quiescent population in the tumor, are known to contribute towards therapy resistance; multiple studies have attributed prognostic properties to markers specific to these cells. In the present study, effort was made to identify oral cancer stem cell-specific markers associated with clinical/pathological prognosticators (angio-lymphatic invasion, T stage, N stage, margin status and risk habits) and/or can be candidates to improve prognostic efficacy. The head and neck cancer stem cell specific/associated marker panel (n = 221) identified in this study includes oncogenes (MYC proto oncogene), cell cycle regulators (CDK1 and Cyclin Dependent Kinase 2), cell surface receptors (Fibroblast Growth Factor receptor), signaling molecules (C-X-C Chemokine Receptor 4, Fas-Associated Death Domain, Fos proto oncogene) and pluripotent genes (NANOG). These markers are associated with poor prognosis (MYC proto oncogene) (Pai et al., 2009; Perez-Sayans et al., 2014) and promote tumorigenic properties such as invasion/migration/self-renewal (MYC proto onco-gene, C-X-C Chemokine Receptor 4, FOS protooncogene) (Muhammad, Bhattacharya, Steele, Phillips, & Ray, 2017; Shrivastava et al., 2015; Yu et al., 2011). Fas associated death domain, an apoptotic modulator
    Fig. 5. Validation of marker expression in patient samples-.
    A. mRNA expression analysis (z-score) of selected markers in recurrent and non-recurrent patients (N-Non recurrence, R-Recurrence). The median expressions of NQO1 and CDK1 in recurrent patients were higher than the non-recurrent patients. B. mRNA expression analysis of selected markers in survived and deceased patients (S-Surviving, D-Deceased). The median expressions of NQO1 and CDK1 in deceased patients were more than the survived patients. C. Percentage of recurrent and non-recurrent patients showing markerhigh expression for each marker D. Percentage of survived and deceased patients with markerhigh expression. E- F. Significant correlation of CDK1 with disease free and overall survival G. NQO1 significantly co-related with overall survival. H- I. The combined expression of CDK1 and NQO1 significantly co-related with disease free and overall survival.
    (Chinnaiyan, O’Rourke, Tewari, & Dixit, 1995) associated with poor disease free/overall survival in oral cancer (Chien et al., 2016; Prapinjumrune et al., 2010), is crucial for embryonic stem cell mediated