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  • br Table br Sensitivity and specificity of

    2020-08-28

    
    Table 6
    Sensitivity and specificity of markers.
    Recurrence
    Markers Sensitivity Specificity % correctly classified Area Under Curve
    Survival
    Markers Sensitivity Specificity % correctly classified Area Under Curve
    AURKA) that correlated with recurrence and/or survival in The Cancer Genome Atlas oral cancer cohort. Analogous to the role of HOX family in regulating differentiation and proliferation during embryogenesis (Morgan, 1997), this family of genes plays a significant role in carci-nogenesis (Bhatlekar, Fields, & Boman, 2014; Shah & Sukumar, 2010), with multiple members being upregulated in oral cancer compared to normal oral mucosa (Bitu et al., 2012; H. Wang et al., 2015). FKBP4 is known to be an Ago2-associated chaperone in embryonic stem Influenza Hemagglutinin (Martinez, Chang, Borrajo Jde, & Gregory, 2013). Although, FKBP4 has not yet been investigated in oral cancer, elevated expression is a poor prognosticator in breast/prostate cancer (Federer-Gsponer et al., 2018; Hong et al., 2017). The significant survival predictors included STAT3, a transcription factor, and UBE2C (Ubiquitin-conjugating enzyme E2CE2), which promote cancer stem cell functions (migration, angio-genesis, inflammation) and maintain the tumor micro-environment in many cancers (Baillie, Tan, & Itinteang, 2017; Ghoshal, Fuchs, & Tanabe, 2016; Shuliang, Lei, Guangwu, & Changjie, 2013; van Ree, Jeganathan, Malureanu, & van Deursen, 2010). EDNRB and PHF5A expression are reported as upregulated in glioblastoma stem cells (Kaur et al., 2010), studies have also attributed poor prognostic behavior in oral cancer (Kaur et al., 2010; Tanaka et al., 2014). AURKA, a cell-cycle modulator (Fu, Bian, Jiang, & Zhang, 2007) and Her2/ERBB2, a proto-oncogene, induced Epithelial Mesenchymal Transition/cancer stem cell properties in hepatic/breast cancers (C. Chen et al., 2017). GINS2, be-longing to GINS family of proteins and PHF5A, apart from being pre-dictors, were also associated with clinico-pathological features (X. Chen et al., 2015; Neganova et al., 2014; Zhang et al., 2013). These markers can be evaluated further for their role as accurate adjunct prog-nosticators to the existing clinico-pathological parameters.
    Initial validation in oral cancer patients by expression profiling identified a subset of these markers as highly significant; NQO1, CDK1, RIT1 being the major candidates. NQO1, encoding for NAD(P) H-qui-nine oxidoreductase 1, a drug metabolizing enzyme, has been shown to be crucial for susceptibility to carcinogenesis. Loss of NQO1 has been shown to reduce ALDH1A1 activity (Madajewski, Boatman, Chakrabarti, Boothman, & Bey, 2016), ALDH1A1 being one of the major cancer stem cell markers in oral cancer. Apart from poly-morphism in NQO1 indicating high risk of oral cancer and non-small cell lung cancer development, NQO1 maintains the cancer stem cell population in the latter (Butsri et al., 2017; Z. Li et al., 2015; Ma et al., 2014; Yang et al., 2014). RIT1, a member of Ras family, plays definitive role in proliferation, differentiation, survival apart from regulating the 
    transcriptional activity of SOX2 (Mir, Cai, & Andres, 2017). Mutation in RIT1 is associated with a subset of lung adenocarcinoma and further-more, RIT1 levels are inversely correlated with survival in endometrial cancer (Berger et al., 2014; Xu et al., 2015). Association with the clinicopathological characteristics identified CDK1 as a marker asso-ciated with nodal metastasis, margin status and advanced pathological characteristics. Blockage of CDK1 in hepatocellular carcinoma has re-sulted in enhance targeting of cancer stem cells by Sorafenib (Wu et al., 2018). It has also been shown that CDK1 interacts with SOX2 in order to promote its tumorigenic potential in melanoma (Ravindran Menon et al., 2018). Given these evidences, the marker panel, as indicated by the initial validation, can be further explored for their clinical utility.
    Recurrence or relapse of the tumor is driven by the ability of the cells to initiate carcinogenesis either in the same site as the primary tumor or at a distant site by metastasis. Tumor initiation and drug re-sistance being the primary attributes of the cancer stem cells, the pre-sence of specific markers may signify recurrence and poor survival. This study identified a panel of 12 cancer stem cell specific or associated markers that were differentials in recurrent oral cancer patients and/or were survival predictors. Validation of a subset of these markers in the patients, some of them not identified in oral cancer previously, in-dicated the significance of this panel. The profiling of these markers in surgical tissue/biopsy can be a predictor of the patient susceptibility to recurrence/poor survival; their clinical utility as accurate prog-nosticators, in their individual as well as in a combinatorial capacity, needs to be assessed through a large scale validation study.