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  • br Cutoff was defined by Yoden s

    2020-03-17


    Cutoff was defined by Yoden's index by maximizing values of sensitivity+specificity-1. a, b, c,: clinically measured biomarkers. b: 36 controls vs. 97 GC. c: 17 controls vs.90 GC.
    morphology [3]. Early detection and diagnosis is crucial to reduce cancer related deaths. In contrast to single tissue biopsy, blood carries informa-tion from cancer Loxapine Succinate even located at distinct metastatic site, which re-flects the overall change of a disease. Upon cancer development and progression, cancer cells secrete proteins into the microenvironment and bloodstream; when tumours grow, the apoptotic and necrotic cells are likely to release numerous proteins into the circulating blood; additionally, cancer systemically elicits an immune response. All of these processes generate circulating proteins as a rich source for bio-markers. Therefore, we measured proteins that are either secreted or lo-cated in cytoplasm or involved in immune response.
    Applying multiplex PEA technology, we analysed the levels of 316 proteins in serum and 245 in tissue specimens from 100 patients with gastric cancer and 50 controls, and identified a combination of 19 poten-tial serum protein biomarkers that distinguish patients with gastric ad-enocarcinoma from cancer free controls. The proteins significantly altered in serum may not be significant in tissue, vice versa. The 19-protein signature determined by elastic-net logistic regression 
    enhanced the diagnostic performance for the whole serum cohort to an AUC of 0·99, a sensitivity of 93% and a specificity of 100%. It also sat-isfactory distinguishes the GC patients at TNM I-II stage and patients with high MSI status from controls.
    Most of the 19 proteins are secreted. Apart from the clinically used biomarker CEACAM5, eight proteins have been reported for their clini-cal significances in both GC blood and tumour tissue, including MMP1 [29–31], MSLN [32–34], CA9 [35–37], CCL20 [38–40], SCF [41,42], TGF alpha [43–45], IGF-1 [46,47], and MMP10 [48]. The first four proteins were also found significantly increased in both GC serum and tumour tissue as analysed by univariate analysis in the present cohort, and SCF, TGF alpha, and MMP10 were significantly altered only in GC tissues, whereas IGF-1 were not changed in neither serum nor tissue.
    A
    Serum_TNM I-II vs. Ctrl
    GCNT1
    DCBLD2
    SLAMF8
    SLITRK2
    MMP1
    NTRK3
    CSF1
    DDAH1 AR
    log2 Fold Change (Pre_TNM I−II/Ctrl) 
    B
    Serum_TNM I-II vs. Ctrl
    Sensitivity 0.50
    19-protein signature FL1I
    CDCP1
    SCF
    PPIA
    MMP1
    TGF alpha
    MSLN
    DDAH1
    HMOX1
    CEACAM5
    APBB1IP
    IGF1
    KAZALD1
    ADAMTS15
    1−Specificity
    C Serum_MSI-H vs. Ctrl 
    Serum_MSI-H vs. Ctrl
    values) 3
    GCNT1
    SYND1
    COL4A1 MSLN CXCL11
    CXCL9 AR
    MICAB 
    Sensitivity 
    19-protein signature
    FL1I
    PPIA
    MMP1
    TGF alpha
    MSLN
    DDAH1
    HMOX1
    CEACAM5
    APBB1IP
    IGF1
    log2 Fold Change (Pre−MSI-H/Ctrl) 
    KAZALD1
    ADAMTS15
    1−Specificity
    Fig. 4. Protein levels in serum samples from GC patients at TNM I-II stage or with high microsatellite instability (MSI) status. (A) Volcano plot showing the comparison of protein levels between patients at TNM I-II stage and controls. (B) ROC curves for the 19-serum protein signature overlaid with each individual protein showing the diagnostic capacity of GC at TNM I-II stage versus controls. (C) Volcano plot showing the comparison of protein levels between patients with MSI-H and controls. (D) ROC curves for the 19-serum protein signature overlaid with each individual protein showing the diagnostic capacity of GC with MSI-H status versus controls. Points in plots A and C having absolute log fold-change ≥0·5 and false discovery rate adjusted p-value b0·05 are Reversion mutation shown in red, with absolute log fold-change b0·5 and p-value b0·05 are in black, with absolute log fold-change b0·5 and p-value ≥0·05 are in gray, and the rest are in orange.