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    • We compared only the diagnostic value of

    2018-11-13

    We compared only the diagnostic value of CENPF and HSP60 for early HCC with AFP, because the number of cases with results of IMP-2 autoantibody was insufficient. In shk with total HCC, better performance of autoantibody to CENPF and HSP60 than AFP was shown when comparing early-HCC and all controls (Table 4, Fig. 3A–D), with AUC values of 0.826, 0.764 and 0.749, respectively. However, for distinguishing early-HCC from liver cirrhosis or liver cirrhosis plus chronic hepatitis, the AUC values of autoantibody to CENPF or HSP60 were similar with that of AFP (Table 4). The prevalence of autoantibody positivity to CENPF and HSP60 was significantly higher than that of AFP positivity in HCCs with tumor stage of BCLC A (p<0.001) (Supplementary Table 7), suggesting a higher diagnostic value of autoantibody for early HCC compared with the AFP. Specifically, 73.6% and 79.3% cases of early HCC with AFP negativity were seropositive for autoantibody to CENPF or HSP60, with AUC values of 0.828 and 0.779, respectively (Table 5, Fig. 3D). These data indicated that the TAAs could be used as a complement for AFP in the diagnosis of AFP-negative early HCC to improve the detection rate. Combined autoantibody to CENPF with AFP improved the ability to distinguish HCC from all controls, with the AUC value of 0.894, or with sensitivity of 88.7% and specificity of 68.8% in the diagnosis of HCC (Fig. 3A, C); and with AUC of 0.882, or with sensitivity of 86.7% and specificity of 68.8% in the diagnosis of HCC at an early stage (Fig. 3B, D). To explore the possible mechanism underlying the occurrence of autoantibody to CENPF in HCC, we analyzed the expression level and cellular localization of CENPF in HCC with various levels of autoantibody to CENPF. IHC analysis was performed on five HCC cases with high levels of serum autoantibody to CENPF (signal intensity more than 4000) and five HCC cases with negative serum autoantibody to CENPF (signal intensity less than 500). The results showed that in all HCC cases evaluated, CENPF was found in the cytoplasm or nucleus. However, overexpression of CENPF was observed in tumor tissue of all HCC cases with high levels of serum autoantibody to CENPF, while low or no CENPF expression was observed in the tumor tissue of all HCC cases with low levels of serum autoantibody to CENPF (Supplementary Fig. 2). The data suggest that the elevated CENPF autoantibody may have resulted from overexpression of CENPF protein.
    Discussion Although there has been an increase in the number of reports of TAAs in various types of tumor including HCC (Yau et al., 2013; Werner et al., 2015; Lacombe et al., 2014), the potential value of autoantibodies in the early diagnosis of HCC remains unclear. The major concern is short-day plants the majority of studies initially screen small sample sizes without validation by large-scale samples. In the present study, using high throughput screening and clinical validation, we reported here a series of TAAs, which might be valuable markers for early detection of HCC. Simultaneous clinical validation of dozens of candidate bio-markers with large-scale samples is extremely difficult. It is almost impossible to conduct large-scale screening and validation studies for specific tumor markers. The traditional techniques such as ELISA, Western Blot analysis, and radioimmunoassays which require relatively large quantities of antigen and patient samples are of limited use when performing large-scale clinical validations (Robinson et al., 2002), especially when performing numerous simultaneous validations. In the present study, we believe that we have identified for the first time, a series of TAAs in HCC using SERPA analysis with total protein extracted from tumor tissue as antigen library. We have also validated the diagnostic value of candidate TAAs compared with that of AFP in a large cohort of early HCC. Twelve of the 22 candidate TAAs were identified with significance differences between HCC and controls. Five of the 12 screened TAAs have been reported previously in HCC or other cancers, including IMP-2 (Zhang and Chan, 2002), CRT (Pekarikova et al., 2010), ENO1 (Takashima et al., 2005), CENPF (Liu et al., 2012), and HSP60 (He et al., 2007), whereas the other seven TAAs in HCC are reported here for the first time, to the best of our knowledge. Three TAAs, CENPF, HSP60, and IMP-2 showed promise for diagnosis of HCC and early HCC, with an AUC value of more than 0.7, a recognized standard for biomarkers, which have a promising diagnostic value in general (Shen et al., 2012). However, the fact that the majority of screened TAAs were identified with low value for diagnosis suggests the importance of high throughput clinical evaluation of the candidate TAAs.