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  • br Correlation of markers with survival and clinico

    2020-08-28


    3.3.4. Correlation of markers with survival and clinico-pathological parameters
    In the oral cancer cohort, based on the information available for follow up in 313 patients, 133 cases were disease free, while 91 cases developed recurrence (Supplementary Table-5). It is known that in oral cancer, advanced stage, recurrence and positive margins correlated with disease free survival. Evaluation in the oral cancer cohort showed 8 genes (HOXA1, NQO1, RIT1, CDK1, FKBP4, GINS2, PHF5 A and ERBB2) that correlated with poor disease free survival (p < 0.05). Among these genes, HOXA1, NQO1, RIT1, FKBP4 and ERBB2 showed > Clozapine-N oxide 2 fold Clozapine-N oxide in recurrent patients and CDK1, GINS2, HOXA1, NQO1, RIT1 and FKBP4 showed significant expression in re-current patients (p < 0.05) (Fig. 3 A–H) (Table 3). These eight markers associated with poor disease-free survival were selected and analysed 
    further.
    The expression patterns of the eight (CDK1, HOXA1, NQO1, RIT1, FKBP4, GINS2, PHF5 A and ERBB2) markers were correlated with smoking habits, T stage, N stage, primary tumor site and margin status. Increased alteration (15%) of RIT1 was found in patients with excessive smoking habit (> 50 packs) than the patients who smoke < 50 packs (5%, p < 0.05). The expression of FKBP4 (13%) was more altered in N + patients than N0 patients (6%, p < 0.05), while CDK1 and GINS2 markers were more altered in patients with positive margin status. Increased alteration of PHF5A expression correlated with extra capsular spread in patients (16% vs 6%, p < 0.05), while CDK1 and FKBP4 markers were more altered in patients with angio lymphatic invasion (p < 0.05) (Table 4). A three-way analysis to evaluate the effect of these markers on the prognostic efficacy of the clinical characteristics was also carried out. This indicated that alterations in RIT1 expression in patients with high risk smoking habits (> 50 packs/year) leads to poor disease free sur-vival (p = 0.00009), while an increase in alteration of CDK1 in ad-vanced T stage, N stage, smoking habit, with positive margin, leads to poor disease free survival (p < 0.05). Alteration of GINS2 and PHF5A expression in patients with advanced T stage, and alteration of PHF5A in patients with positive margins and advanced N stage also lead to poor disease free survival(p < 0.05) (Table 4). A similar correlation carried out between pathological parameters (angio-lymphatic inva-sion, perineural invasion and extra capsular spread), marker expression and survival indicated that alterations in expression of FKBP4 in pa-tients with angio-lymphatic invasion were associated with poor survival (p < 0.05), while CDK1 alterations in patients with angio-lymphatic invasion, extra capsular spread and perineural invasion was prognostic of poor disease free survival (p < 0.05) (Table 4).
    The combination of this panel of 8 markers, HOXA1, FKBP4, RIT1, NQO1, CDK1, GINS2, PHF5 A and ERBB2 led to poor overall survival (p = 0.001) and disease free survival (p = 0.0000002); alterations in the transcript levels of this marker combination reduces the survival from 89 to 28 months (Fig. 4 A–B). This subset of survival predictors in combination with the markers associated with recurrence formed a cancer stem cell-specific marker panel (n = 12; HOXA1, FKBP4, RIT1, NQO1, CDK1, GINS2, PHF5 A, ERBB2, UBE2C, EDNRB, STAT3, AURKA) for prognostication in oral cancer.
    S. Mohanta et al.
    FDR q-value
    p-value
    Genes in Overlap (k)
    fibrosis and metastasis.
    of caspases.
    Description
    Genes defining epithelial-mesenchymal transition, as in wound healing,Genesinvolvedinp53pathwaysandnetworks.GenesregulatedbyNF-kBinresponsetoTNF[GeneID=7124]. Genes defining late response to estrogen.Genesup-regulatedinresponsetolowoxygen levels (hypoxia).Genesmediatingprogrammedcelldeath(apoptovarallis)byactivationGenesup-regulatedbyactivationofthePI3K/AKT/mTORpathway.Genesdefiningearlyresponsetoestrogen.Genesencodingproteinsinvolvedinglycolysisandgluconeogenesis.Genesdown-regulatedinresponsetoultraviolet(UV)radiation.
    Table 3
    mRNA expression and co-relation with survival in The Cancer Genome Atlas (TCGA) Oral cancer cohort.
    Gene Symbol Regulation p value of m TCGA TCGA TCGA
    RNA Oral Survival, Survival,
    Rec vs OS, DFS,
    Dis free p value p value
    Fold
    # HOXA1, NQO1, RIT1, FKBP4 were the genes which showed significantly > 2 fold expression in recurrent patients and associated with poor disease free survival. So they are the markers involved both in recurrence and survival of the patients.
    # AURKA, STAT3, EDNRB and UBE2C showed significantly > 2 fold expression in the recurrent patients. So these genes are associated exclusively with re-currence.